Kinetic resolutions of chiral 2-and 3-substituted carboxylic acids

ABSTRACT

One aspect of the present invention relates to a method for the kinetic resolution of racemic and diastereomeric mixtures of chiral compounds. The critical elements of the method are: a non-racemic chiral tertiary-amine-containing catalyst; a racemic or diastereomeric mixture of a chiral substrate, e.g., a cyclic carbonate or cyclic carbamate; and a nucleophile, e.g., an alcohol, amine or thiol. A preferred embodiment of the present invention relates to a method for achieving the kinetic resolution of racemic and diastereomeric mixtures of derivatives of α- and β-amino, hydroxy, and thio carboxylic acids. In certain embodiments, the methods of the present invention achieve dynamic kinetic resolution of a racemic or diastereomeric mixture of a substrate, i.e., a kinetic resolution wherein the yield of the resolved enantiomer or diastereomer, respectively, exceeds the amount present in the original mixture due to the in situ equilibration of the enantiomers or diastereomers under the reaction conditions prior to the resolution step.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/919,371, filed Jul. 31, 2001 now U.S. Pat. No. 6,562,966; whichclaims the benefit of the filing date of U.S. Provisional PatentApplication serial No. 60/222,145, filed Jul. 31, 2000; and UnitedStates Provisional Patent Application serial No. 60/253,172, filed Nov.27, 2000.

GOVERNMENT SUPPORT

The invention described herein was supported in part by NationalInstitutes of Health Grant Number NIH GM61591. The U.S. Government hascertain rights to this invention.

BACKGROUND OF THE INVENTION

The demand for enantiomerically pure compounds has grown rapidly inrecent years. One important use for such chiral, non-racemic compoundsis as intermediates for synthesis in the pharmaceutical industry. Forinstance, it has become increasingly clear that enantiomerically puredrugs have many advantages over racemic drug mixtures. These advantages(reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp.46-79) include the fewer side effects and greater potency oftenassociated with enantiomerically pure compounds.

Traditional methods of organic synthesis were often optimized for theproduction of racemic materials. The production of enantiomerically purematerial has historically been achieved in one of two ways: use ofenantiomerically pure starting materials derived from natural sources(the so-called “chiral pool”); and the resolution of racemic mixtures byclassical techniques. Each of these methods has serious drawbacks,however. The chiral pool is limited to compounds found in nature, soonly certain structures and configurations are readily available.Resolution of racemates, which requires the use of resolving agents, maybe inconvenient and time-consuming. Furthermore, resolution often meansthat the undesired enantiomer is discarded, thus decreasing efficiencyand wasting half of the material.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method for the kineticresolution of racemic and diastereomeric mixtures of chiral compounds.The critical elements of the method are: a non-racemic chiraltertiary-amine-containing catalyst; a racemic or diastereomeric mixtureof a chiral substrate, e.g., a cyclic carbonate or cyclic carbamate; anda nucleophile, e.g., an alcohol, amine or thiol. A preferred embodimentof the present invention relates to a method for achieving the kineticresolution of racemic and diastereomeric mixtures of derivatives of α-and β-amino, hydroxy, and thio carboxylic acids. In certain embodiments,the methods of the present invention achieve dynamic kinetic resolutionof a racemic or diastereomeric mixture of a substrate, i.e., a kineticresolution wherein the yield of the resolved enantiomer or diastereomer,respectively, exceeds the amount present in the original mixture due tothe in situ equilibration of the enantiomers or diastereomers under thereaction conditions prior to the resolution step.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the structures of certain catalysts used in the methodsof the present invention, and their abbreviations herein.

FIG. 2 depicts the structures of certain catalysts used in the methodsof the present invention, and their abbreviations herein.

FIG. 3 depicts two embodiments of the methods of the present invention.

FIG. 4 tabulates the yields and enantiomeric excesses of the productsand unreacted starting materials of kinetic resolutions of variousdioxolanediones.

FIG. 5 tabulates the yields and enantiomeric excesses of the productsand unreacted starting materials of kinetic resolutions of variousdioxolanediones.

FIG. 6 tabulates the yields and enantiomeric excesses of the productsand unreacted starting materials of kinetic resolutions of variousdioxolanediones.

DETAILED DESCRIPTION OF THE INVENTION

The ability to selectively transform a racemic or diastereomeric mixtureof a chiral compound to an enantiomerically- ordiastereomerically-enriched or an enantiomerically- ordiastereomerically-pure chiral compound has broad applicability in theart of organic chemistry, especially in the agricultural andpharmaceutical industries, as well as in the polymer industry. Asdescribed herein, the present invention relates to methods for thekinetic resolution of racemic and diastereomeric mixtures of chiralcompounds. As set forth in greater detail below, the primaryconstituents of the methods are: a non-racemic chiraltertiary-amine-containing catalyst; a racemic or diastereomeric mixtureof a chiral substrate, e.g., a cyclic carbonate or cyclic carbamate; anda nucleophile, e.g., an alcohol or thiol. In the methods of the presentinvention, said nucleophile selectively attacks one of thediastereomeric transition states or intermediates formed from thecatalyst and substrate, generating an enantiomerically- ordiastereomerically-enriched or an enantiomerically- ordiastereomerically-pure chiral product.

Catalytic Asymmetric Synthesis of α-Hydroxy Carboxylic Acids

Racemic 5-alkyl-1,3-dioxolane-2,4-diones (2) can be prepared readilyfrom the corresponding racemic α-hydroxy carboxylic acids (1). Toyooka,K. et al. Heterocycles 1989, 29, 975-978. The successful development ofan efficient kinetic resolution of 2 has lead to an attractive catalyticpreparation of chiral non-racemic α-hydroxy carboxylic acid derivatives,which are versatile chiral building blocks in asymmetric synthesis (SeeScheme 1). Lee, J. B. et al. Tetrahedron 1967, 23, 359-363; Mori, K. etal. Tetrahedron 1979, 35, 933-940; and Grieco, P. A. et al. J. Org.Chem. 1985, 50, 3111-3115.

For example, we have investigated the kinetic resolution of5-phenyl-1,3-dioxolane-2,4-dione (5), using cinchona-alkaloid-catalyzedalcoholysis. As illustrated in Scheme 2, we found that the racemicstarting material (5) can be converted to a single product in 65% yieldin excellent enantiomeric excess (97%). Apparently, the kineticresolution of 5 occurs in the most desirable fashion, i.e., dynamickinetic resolution. Rapid epimerization at the stereocenter of thestarting material allows the establishment of an equilibrium between thetwo enantiomers of the starting material (5a and 5b). The coupling ofthis equilibrium with a selective conversion of one of the twoenantiomers leads to the conversion of the racemic mixture to a singleproduct with a yield greater than 50% and in high enantiomeric excess.Acting as both a Bronsted base and a Lewis base, the cinchona alkaloidappears to catalyze both the epimerization and the alcoholysisreactions. Based on the observed enantiomeric excess of the product, theselectivity factor (k_(fast)/k_(slow)) for the reaction is greater than50. As demonstrated herein, the dynamic kinetic resolution overcomestraditional drawbacks associated with a standard kinetic resolution,such as a maximum yield of 50% and the eventual need to separate amixture of compounds, e.g., the product from unreacted startingmaterial. All signs indicate that this reaction can be developed intoone of the most practical methods for the asymmetric synthesis ofoptically active α-hydroxy carboxylic acid derivatives. Kitamura, M. etal. J. Am. Chem. Soc. 1988, 110, 629-631; Mashima, K. et al. J. Org.Chem. 1994, 59, 3064-3076; Burk, M. J. et al. J. Am. Chem. Soc. 1998,120, 4345-4353; Wang, Z. et al. Tetrahedron Lett. 1998, 39, 5501-5504;Chiba, T. et al. Tetrahedron Lett. 1993, 34, 2351-2354; and Huerta, F.F. et al. Org. Lett. 2000, 2, 1037-1040.

Catalytic Asymmetric Synthesis of α-Amino Carboxylic Acids

Acyl transfer reactions utilize cheap reagents to transform readilyavailable starting materials into useful and easily purified products.These characteristics in combination with high enantioselectivity haveenabled acyl transfer reactions catalyzed by enzymes such as lipase andesterase to become highly valuable methods for asymmetric synthesis. Thedevelopment of synthetic catalysts to mimic lipase/esterase with thegoal of further expanding the scope and synthetic utility of asymmetricacyl transfer catalysis is of both conceptual and practicalsignificances for asymmetric catalysis. Although several effectivesynthetic catalysts for the kinetic resolution of racemic alcohols haverecently emerged, efforts to develop small molecule-catalyzed kineticresolutions of racemic carbonyl derivatives have met with limitedsuccess despite their great potential in asymmetric synthesis. We reporthere an exceedingly general and highly enantioselective kineticresolution of urethane-protected α-amino acid N-Carboxy Anhydrides(UNCA) that generates optically active α-amino acids derivativessuitable for further synthetic elaborations such as peptide synthesis.

Encouraged by our discovery of highly enantioselective alcoholysis forthe desymmetrization of meso anhydrides, we became particularlyinterested in the kinetic resolution of racemic carbonyl compounds suchas the urethane-protected α-amino acid N-carboxy anhydrides (UNCA, 2)via cinchona alkaloid-catalyzed alcoholysis alcoholysis to generateoptically active carbamate-protected α-amino acids derivatives (Scheme3). UNCAs (2) are easily accessible from racemic amino acids (1), stablefor long term storage. Their alcoholysis generates thecarbamate-protected amino ester 3 and the environmentally benign CO₂.Moreover, the remaining enantiomerically enriched UNCA (2a) after thekinetic resolution can be converted to the carbamate-protected aminoacid (4) by hydrolysis (Scheme 3). The reaction mixture, consisting ofthe Bronsted basic amine catalyst, the acidic amino acid (4) and theneutral amino ester (3), can be separated using simple procedures togive 3 and 4 as well as the recovered catalyst in desired chemical andoptical purity.

Racemic N-Cbz-phenylalanine NCA (2a), prepared from racemic phenylalanine in 72% yield for two steps, was employed as a model substrate inthe initial evaluation of key reaction parameters to establish optimalconditions for the kinetic resolution. Reaction of 2a with methanol(0.55 equiv) at room temperature in ether in the presence of (DHQD)₂AQN(10 mol %) and molecular sieves (4 Å) provided the desired methyl ester3a in 82% ee at 40% reaction conversion, indicating that the kineticresolution proceeded with a selectivity factor (s) of 16 (entry 1, Table1). Following this promising lead, we subsequently found that theenantioselectivity of the kinetic resolution can be dramaticallyimproved by carrying out the (DHQD)₂AQN-catalyzed alcoholysis at lowtemperature. At −60° C. the enantioselectivity of the kinetic resolutionwas found to reach a level (s=79, entry 2, Table 1) comparable to thatof an efficient enzyme-catalyzed kinetic resolution.

TABLE 1 Kinetic Resolution of UNCA 2a with Cinchona Alkaloids^(a)

Entry Catalyst T/° C. Conv/%^(b) ee of 3a/%^(c,d) s^(e) 1 A 25 42 80 162 A −60 50 92 79 3 B −60 45 91 47 4 C −60 44 86 27 ^(a)The reaction wasperformed with 2a (0.1 mmol) in ether (7.0 mL). ^(b)Determined by GCanalysis, see Supporting Information. ^(c)Determined by HPLC analysis,see Supporting Information. ^(d)The absolute configuration of 3a wasdetermined by comparison of its sign of optical rotation with theliterature value; see Supporting Information. ^(e)The selectivity factors was calculated using the equation s = k_(f)/k_(s) = ln[1 − C(1 +ee)]/ln[1 − C(1 − ee)], where ee is the percent enantiomeric excess ofthe product (3a) and C is the conversion. Catalyst A = (DHQD)₂AQNCatalyst B = DHQD-PHN Catalyst C = Quinidine

A variety of natural and modified cinchona alkaloids were screened fortheir abilities to mediate the kinetic resolution of 2a via alcoholysis.The results are summarized in Table 1. While (DHQD)₂AQN, a modifiedbiscinchona alkaloid, stands as the most effective in our catalystscreening, a modified monocinchona alkaloid, DHQD-PHN, is also found tobe a highly effective catalyst (entry 3, Table 1). Particularly notable,however, is the finding that an excellent enantioselectivity could beachieved with quinidine, a natural cinchona alkaloid (entry 4, Table 1).Interestingly, under the same condition, reactions with other closelyrelated chiral and achiral amines, including (DHQD)₂PYR, (DHQD)₂PHAL,DHQD-MEQ, DHQD-CLB and quinuclidine, gave only minuscule conversions(1-4%).

The practical features of the kinetic resolution were demonstrated in apreparative scale resolution of 2a (4.0 mmol). The modified cinchonaalkaloid-catalyzed alcoholysis of 2a proceeded cleanly to allow theisolation of both ester 3a and acid 4a in nearly quantitative yields andthe quantitative recovery of the catalyst in pure form using a simpleextractive procedure (Table 2). The recovered catalyst can be useddirectly for another preparative-scale resolution of 2a, showing nodetectable deterioration in catalytic activity and selectivity (Table2).

TABLE 2 Preparative Scale Kinetic Resolution of 2a with Recycled(DHQD)₂AQN

ee^(b) (yield^(c))/% Cycle Conv^(a) 3a 4a s 1 51 93 (48) 97 (48) 114 252 91 (49) 98 (47) 97 ^(a)The conversion, calculated using the equation:C = 100 × ee_(2a)/(ee_(3a) + ee_(2a)), is consistent with thatdetermined experimentally, see supporting information ^(b)For eeanalysis and absolute configuration determination, see SupportingInformation. ^(c)Isolated yield.

The scope of the reaction was found to be highly general. Clean kineticresolutions of extraordinarily high enantioselectivities were attainablewith an extensive range of UNCAs (Table 3). Following the sameextractive procedure used for the isolation of 3a and 4a, the opticallyactive α-amino esters 3 and amino acids 4 derived from kineticresolutions of racemic 2 were routinely obtained in a combined yield ofgreater than 90%. Both α-alkyl- and aryl-substituted UNCAs were resolvedwith exceptional enantioselectivities. The presence of heteroatoms andheterocycle in the substrates has no negative effect on the efficiencyof the kinetic resolution. Even with a substrate bearing a α-branchedalkyl side chain, the resolution can be accomplished with asynthetically useful enantioselectivity at 0° C. (entry 8, Table 3).Furthermore, the reaction is remarkably tolerant of structuralvariations of the protecting group, thus permitting the efficientsyntheses of CBz-, Alloc-, Boc-, and even the base-sensitiveFmoc-protected amino acids and esters in high optical purity andexcellent yields. Among all the cases examined, (R)-3 and (S)-4 wereobtained consistently from the (DHQD)₂AQN-catalyzed kinetic resolutionof racemic-2 (a-c, e, g-m).

TABLE 3 Kinetic Resolution of UNCA (2) via Modified CinchonaAlkaloids-Catalyzed Alcoholysis^(a) UNCA 2 temp Time conv ee^(b)(yield)/%^(c) entry R P (° C.) (h) (%) 4 3 s 1 a PhCH₂ ^(d) Z −60 17 5197 (48) 93 (48) 114 2 b 4-F—C₆H₄CH₂ Z −78 31 50 92 (42) 92 (48) 79 3 c4-Cl—C₆H₄CH₂ Z −60 18 52 97 (43) 88 (52) 59 4 d 4-Br—C₆H₄CH₂ Z −78 45 5397^(g) (39) 87^(g) (51) 66 5 e 2-thienylmethyl Z −78 37 50 94 (47)^(h)94 (49)^(h) 115 6 f CH₃(CH₂)₅ Z −60 72 51 94^(g) (49) 91^(g) (49) 78 7 gBnOCH₂ Z −78 22 51 91 (44) 89 (49) 58 8 h (CH₃)₂CH^(e) Z 0 16 59 96 (40)67 (58) 19 9 i Ph^(f) Z −78 85 46 84 (46) 97 (45) 170 10 j 4-MeO—C₆H₄^(f) Z −78 25 56 95 (43)^(h) 74 (56)^(h) 23 11 k PhCH₂ Fmoc −78 46 51 96(47) 92 (50) 93 12 l PhCH₂ Boc −40 15 59 98 (41) 67 (56) 22 13 m PhCh₂Alloc −60 15 50 91 (45) 91 (45) 67 14 n PhCH₂CH₂ Alloc −60 36 54 96^(g)(41) 81^(g) (53) 35 ^(a)Unless otherwise noted, the reaction wasperformed by treatment of 2 (0.1 mmol) with (DHQD)₂AQN (10 mol %) andmethanol (0.52-1.0 eq.) in ether (7.0 mL). ^(b)For details of eeanalysis and absolute configuration determination for 3 and 4, seeSupporting Information. ^(c)Unless otherwise noted, Isolated yield usingan extractive procedure. ^(d)The reaction was performed with 4.0 mmol of2a. ^(e)The reaction was catalyzed by DHQD-PHN (20 mol %). ^(f)0.55 eqof ethanol was used. ^(g)The absolute configuration was not determined.^(h)isolated yield using a chromatographic purification.

Importantly, our results indicate that we have discovered a practicalmethod for the preparation of optically pure chiral α-amino acids.Moreover, we believe our method compares favorably to other catalyticmethods for chiral amino acid synthesis. See Corey, E. J. et al.Tetrahedron Lett. 1998, 39, 5347-5350; Corey, E. J. et al. J. Am. Chem.Soc. 1997, 119, 12414-12415; Ooi, T. et al. J. Am. Chem. Soc. 2000, 122,5228-5229; Ooi, T. et al. J. Am. Chem. Soc. 1999, 121, 6519-6520;O'Donnell, M. J. et al. Tetrahedron Lett. 1998, 39, 8775-8778; Porter,J. R. et al. J. Am. Chem. Soc. 2000, 122, 2657-2658; Krueger, C. A. etal. J. Am. Chem. Soc. 1999, 121, 4284-4285; Sigman, M. S. et al. J. Am.Chem. Soc. 1998, 120, 5315-5316; Sigman, M. S. et al. J. Am. Chem. Soc.1998, 120, 4901-4902; Ishtani, H. et al. Angew. Chem. Int. Ed. 1998, 37,3186-3188; Corey, E. J. et al. Org. Lett. 1999, 1, 157-160; Burk, M. J.et al. J. Am. Chem. Soc. 1998, 120, 657-663; Ferraris, D. et al. J. Am.Chem. Soc. 1998, 120, 4548-4549; and Fang, X. et al. J. Org. Chem. 1999,64, 4844-4849. Further, our method generates amino acids protected witha group that is commonly used in peptide synthesis, i.e., the so-calledZ or Cbz group. Other catalytic methods developed for the preparation ofoptically active α-amino acids often require special protecting groupsthat must ultimately be converted to a more suitable protecting group,such as Cbz. Finally, the asymmetric catalyst, e.g., (DHQD)₂AQN, can berecycled via simple acid washing and extraction.

In sum, we have discovered the first effective and general nonenzymaticcatalytic method for the asymmetric synthesis of α-amino acids via akinetic resolution strategy. With its extraordinary enantioselectivityand generality, the kinetic resolution of UNCA (2) via asymmetricalcoholysis catalyzed by cinchona alkaloids provides a highlyenantioselective and reliable catalytic method for the preparation ofoptically active amino acid derivatives that are suitably protected fordirect further synthetic elaborations. The reaction utilizes readilyaccessible substrates, cheap reagents, commercially available as well asfully recyclable catalysts, and simple experimental protocols involvingno chromatography.

Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The term “nucleophile” is recognized in the art, and as used hereinmeans a chemical moiety having a reactive pair of electrons. Examples ofnucleophiles include uncharged compounds such as water, amines,mercaptans and alcohols, and charged moieties such as alkoxides,thiolates, carbanions, and a variety of organic and inorganic anions.Illustrative anionic nucleophiles include simple anions such ashydroxide, azide, cyanide, thiocyanate, acetate, formate orchloroformate, and bisulfite. Organometallic reagents such asorganocuprates, organozincs, organolithiums, Grignard reagents,enolates, acetylides, and the like may, under appropriate reactionconditions, be suitable nucleophiles. Hydride may also be a suitablenucleophile when reduction of the substrate is desired.

The term “electrophile” is art-recognized and refers to chemicalmoieties which can accept a pair of electrons from a nucleophile asdefined above. Electrophiles useful in the method of the presentinvention include cyclic compounds such as epoxides, aziridines,episulfides, cyclic sulfates, carbonates, lactones, lactams and thelike. Non-cyclic electrophiles include sulfates, sulfonates (e.g.tosylates), chlorides, bromides, iodides, and the like.

The terms “electrophilic atom”, “electrophilic center” and “reactivecenter” as used herein refer to the atom of the substrate that isattacked by, and forms a new bond to, the nucleophile. In most (but notall) cases, this will also be the atom from which the leaving groupdeparts.

The term “electron-withdrawing group” is recognized in the art and asused herein means a functionality which draws electrons to itself morethan a hydrogen atom would at the same position. Exemplaryelectron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl,trifluoromethyl, —CN, chloride, and the like. The term“electron-donating group”, as used herein, means a functionality whichdraws electrons to itself less than a hydrogen atom would at the sameposition. Exemplary electron-donating groups include amino, methoxy, andthe like.

The terms “Lewis base” and “Lewis basic” are recognized in the art, andrefer to a chemical moiety capable of donating a pair of electrons undercertain reaction conditions. Examples of Lewis basic moieties includeuncharged compounds such as alcohols, thiols, olefins, and amines, andcharged moieties such as alkoxides, thiolates, carbanions, and a varietyof other organic anions.

The terms “Lewis acid” and “Lewis acidic” are art-recognized and referto chemical moieties which can accept a pair of electrons from a Lewisbase.

The term “meso compound” is recognized in the art and means a chemicalcompound which has at least two chiral centers but is achiral due to aninternal plane, or point, of symmetry.

The term “chiral” refers to molecules which have the property ofnon-superimposability on their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. A “prochiral molecule” is an achiral molecule which hasthe potential to be converted to a chiral molecule in a particularprocess.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement oftheir atoms or groups in space. In particular, the term “enantiomers”refers to two stereoisomers of a compound which are non-superimposablemirror images of one another. The term “diastereomers”, on the otherhand, refers to the relationship between a pair of stereoisomers thatcomprise two or more asymmetric centers and are not mirror images of oneanother.

Furthermore, a “stereoselective process” is one which produces aparticular stereoisomer of a reaction product in preference to otherpossible stereoisomers of that product. An “enantioselective process” isone which favors production of one of the two possible enantiomers of areaction product. The subject method is said to produce a“stereoselectively-enriched” product (e.g., enantioselectively-enrichedor diastereoselectively-enriched) when the yield of a particularstereoisomer of the product is greater by a statistically significantamount relative to the yield of that stereoisomer resulting from thesame reaction run in the absence of a chiral catalyst. For example, anenantioselective reaction catalyzed by one of the subject chiralcatalysts will yield an e.e. for a particular enantiomer that is largerthan the e.e. of the reaction lacking the chiral catalyst.

The term “regioisomers” refers to compounds which have the samemolecular formula but differ in the connectivity of the atoms.Accordingly, a “regioselective process” is one which favors theproduction of a particular regioisomer over others, e.g., the reactionproduces a statistically significant preponderence of a certainregioisomer.

The term “reaction product” means a compound which results from thereaction of a nucleophile and a substrate. In general, the term“reaction product” will be used herein to refer to a stable, isolablecompound, and not to unstable intermediates or transition states.

The term “substrate” is intended to mean a chemical compound which canreact with a nucleophile, or with a ring-expansion reagent, according tothe present invention, to yield at least one product having astereogenic center.

The term “catalytic amount” is recognized in the art and means asubstoichiometric amount relative to a reactant. As used herein, acatalytic amount means from 0.0001 to 90 mole percent relative to areactant, more preferably from 0.001 to 50 mole percent, still morepreferably from 0.01 to 10 mole percent, and even more preferably from0.1 to 5 mole percent relative to a reactant.

As discussed more fully below, the reactions contemplated in the presentinvention include reactions which are enantioselective,diastereoselective, and/or regioselective. An enantioselective reactionis a reaction which converts an achiral reactant to a chiral productenriched in one enantiomer. Enantioselectivity is generally quantifiedas “enantiomeric excess” (ee) defined as follows:

% enantiomeric excess(ee)A=(% enantiomer A)−(% enantiomer B)

where A and B are the enantiomers formed. Additional terms that are usedin conjunction with enatioselectivity include “optical purity” or“optical activity”. An enantioselective reaction yields a product withan e.e. greater than zero. Preferred enantioselective reactions yield aproduct with an e.e. greater than 20%, more preferably greater than 50%,even more preferably greater than 70%, and most preferably greater than80%.

A diastereoselective reaction converts a chiral reactant (which may beracemic or enantiomerically pure) to a product enriched in onediastereomer. If the chiral reactant is racemic, in the presence of achiral non-racemic reagent or catalyst, one reactant enantiomer mayreact more slowly than the other. This class of reaction is termed akinetic resolution, wherein the reactant enantiomers are resolved bydifferential reaction rate to yield both enantiomerically-enrichedproduct and enantimerically-enriched unreacted substrate. Kineticresolution is usually achieved by the use of sufficient reagent to reactwith only one reactant enantiomer (i.e. one-half mole of reagent permole of racemic substrate). Examples of catalytic reactions which havebeen used for kinetic resolution of racemic reactants include theSharpless epoxidation and the Noyori hydrogenation.

A regioselective reaction is a reaction which occurs preferentially atone reactive center rather than another non-identical reactive center.For example, a regioselective reaction of an unsymmetrically substitutedepoxide substrate would involve preferential reaction at one of the twoepoxide ring carbons.

The term “non-racemic” with respect to the chiral catalyst, means apreparation of catalyst having greater than 50% of a given enantiomer,more preferably at least 75%. “Substantially non-racemic” refers topreparations of the catalyst which have greater than 90% ee for a givenenantiomer of the catalyst, more preferably greater than 95% ee.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 of fewer. Likewise, preferred cycloalkylshave from 4-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

Moreover, the term alkyl as used throughout the specification and claimsis intended to include both “unsubstituted alkyls” and “substitutedalkyls”, the latter of which refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, ahalogen, a hydroxyl, a carbonyl, an alkoxyl, and ester, a phosphoryl, anamine, an amide, an imine, a thiol, a thioether, a thioester, asulfonyl, an amino, a nitro, or an organometallic moiety. It will beunderstood by those skilled in the art that the moieties substituted onthe hydrocarbon chain can themselves be substituted, if appropriate. Forinstance, the substituents of a substituted alkyl may includesubstituted and unsubstituted forms of amines, imines, amides,phosphoryls (including phosphonates and phosphines), sulfonyls(including sulfates and sulfonates), and silyl groups, as well asethers, thioethers, selenoethers, carbonyls (including ketones,aldehydes, carboxylates, and esters), —CF₃, —CN and the like. Exemplarysubstituted alkyls are described below. Cycloalkyls can be furthersubstituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls,carbonyl-substituted alkyls, CF₃, CN, and the like.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one double or triple carbon—carbonbond, respectively.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

As used herein, the term “amino” means —NH₂; the term “nitro” means—NO₂; the term “halogen” designates —F, —Cl, —Br or —I; the term “thiol”means —SH; the term “hydroxyl” means —OH; the term “sulfonyl” means—SO₂—; and the term “organometallic” refers to a metallic atom (such asmercury, zinc, lead, magnesium or lithium) or a metalloid (such assilicon, arsenic or selenium) which is bonded directly to a carbon atom,such as a diphenylmethylsilyl group.

an be represented by the general formula:

wherein R₉ is as defined above, and R′₁₁ represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that can be represented by the general formula:

wherein R₉, R₁₀ are as defined above. Preferred embodiments of the amidewill not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R₈, wherein m and R₈ are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carbonyl” is art recognized and includes such moieties as canbe represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈ or apharmaceutically acceptable salt, R′₁₁ represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above. WhereX is an oxygen and R₁₁ or R′₁₁ is not hydrogen, the formula representsan “ester”. Where X is an oxygen, and R₁₁ is as defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR₁₁ is a hydrogen, the formula represents a “carboxylic acid”. Where Xis an oxygen, and R′₁₁ is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X is asulfur and R₁₁ or R′₁₁ is not hydrogen, the formula represents a“thiolester.” Where X is a sulfur and R₁₁ is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X is a sulfur and R₁₁′ ishydrogen, the formula represents a “thiolformate.” On the other hand,where X is a bond, and R₁₁ is not hydrogen, the above formula representsa “ketone” group. Where X is a bond, and R₁₁ is hydrogen, the aboveformula represents an “aldehyde” group.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₈,where m and R₈ are described above.

The term “sulfonate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

The term “sulfate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is as defined above.

The term “sulfonylamino” is art recognized and includes a moiety thatcan be represented by the general formula:

The term “sulfamoyl” is art-recognized and includes a moiety that can berepresented by the general formula:

The term “sulfonyl”, as used herein, refers to a moiety that can berepresented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

The term “sulfoxido” as used herein, refers to a moiety that can berepresented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

A “selenoalkyl” refers to an alkyl group having a substituted selenogroup attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of —Se-alkyl,—Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R₇, m and R₇ being definedabove.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, alkenylamines, alkynylamines, alkenylamides,alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls,metalloalkenyls and metalloalkynyls.

The term “aryl” as used herein includes 4-, 5-, 6- and 7-memberedsingle-ring aromatic groups which may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycle”. Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, halogens, alkyls,alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines,amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇, —CF₃, —CN, or the like.

The terms “heterocycle” or “heterocyclic group” refer to 4 to10-membered ring structures, more preferably 5 to 7 membered rings,which ring structures include one to four heteroatoms. Heterocyclicgroups include pyrrolidine, oxolane, thiolane, imidazole, oxazole,piperidine, piperazine, morpholine. The heterocyclic ring can besubstituted at one or more positions with such substituents as describedabove, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl,amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines,carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The terms “polycycle” or “polycyclic group” refer to two or more cyclicrings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocycles) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino,nitro, thiol, amines, imines, amides, phosphonates, phosphines,carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur, phosphorus and selenium.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Alsofor purposes of this invention, the term “hydrocarbon” is contemplatedto include all permissible compounds having at least one hydrogen andone carbon atom. In a broad aspect, the permissible hydrocarbons includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic organic compounds which can besubstituted or unsubstituted.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms, represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

Catalysts of the Invention

The catalysts employed in the subject methods are non-racemic chiraltertiary amines, phosphines and arsines which present an asymmetricenvironment, causing differentiation between the two enantiomers ordiastereomers of the substrate mixture, i.e., the chiral non-racemiccatalyst preferentially reacts with one enantiomer or diastereomer ofthe substrate mixture. In preferred embodiments, catalysts employed inthe subject methods are non-racemic chiral tertiary amines, e.g.,cinchona alkaloids. In general, catalysts useful in the methods of thepresent invention can be characterized in terms of a number of features.For instance, in preferred embodiments, the catalysts compriseasymmetric bicyclic or polycyclic scaffolds incorporating a tertiaryamine moiety which provide a rigid or semi-rigid environment near theamine nitrogen. This feature, through imposition of structural rigidityon the amine nitrogen in proximity to one or more asymmetric centerspresent in the scaffold, contributes to the creation of a meaningfuldifference in the energies of the corresponding diastereomerictransitions states for the overall transformation. Furthermore, thechoice of substituents on the tertiary amine may also effect catalystreactivity; in general, bulkier substituents are found to provide highercatalyst turnover numbers.

A preferred embodiment for each of the embodiments described aboveprovides a catalyst having a molecular weight less than 2,000 g/mol,more preferably less than 1,000 g/mol, and even more preferably lessthan 500 g/mol. Additionally, the substituents on the catalyst can beselected to influence the solubility of the catalyst in a particularsolvent system. FIGS. 2 and 3 depict preferred embodiments of tertiaryamine catalysts used in the methods of the present invention.

As mentioned briefly above, the choice of catalyst substituents can alsoeffect the electronic properties of the catalyst. Substitution of thecatalyst with electron-rich (electron-donating) moieties (including, forexample, alkoxy or amino groups) may increase the electron density ofthe catalyst at the tertiary amine nitrogen, rendering it a strongerBronsted and/or Lewis base. Conversely, substitution of the catalystwith electron-poor moieties (for example, chloro or trifluoromethylgroups) can result in lower electron density of the catalyst at thetertiary amine nitrogen, rendering it a weaker Bronsted and/or Lewisbase. To summarize this consideration, the electron density of thecatalyst can be important because the electron density at the tertairyamine nitrogen will influence the Lewis basicity of the nitrogen and itsnucleophilicity. Choice of appropriate substituents thus makes possiblethe “tuning” of the reaction rate and the stereoselectivity of thereaction.

Methods of the Invention—Catalyzed Reactions

One aspect of the present invention provides a method for the kineticresolution of racemic or diastereomeric mixtures of a substrate,yielding a single enantiomer or diastereomer, respectively, of theproduct or unreacted substrate or both. The critical elements of themethod are: a non-racemic chiral tertiary-amine-containing catalyst; aracemic or diastereomeric mixture of a chiral substrate, e.g., a cycliccarbonate or cyclic carbamate; and a nucleophile, e.g., an alcohol orthiol. An advantage of this invention is that enantiomerically ordiastereomerically enriched substrates, products or both can be preparedfrom racemic or diastereomeric mixtures of substrates.

In certain embodiments, the methods of the present invention achievedynamic kinetic resolution of a racemic or diastereomeric mixture of asubstrate, i.e., a kinetic resolution wherein the yield of the resolvedenantiomer or diastereomer, respectively, exceeds the amount present inthe original mixture due to the in situ equilibration of the enantiomersor distereomers under the reaction conditions prior to the resolutionstep. An advantage of the dynamic kinetic resolution methods is thatyield losses associated with the presence of an undesired enantiomer ordiastereomer can be substantially reduced or eliminated altogether.Preferred embodiments of the present invention relate to methods forachieving the kinetic resolution of racemic and diastereomeric mixturesof derivatives of α- and β-amino, hydroxy, and thio carboxylic acids.

In general, the invention features a stereoselective ring openingprocess which comprises combining a nucleophile, e.g., an alcohol, thiolor amine, a racemic or diastereomeric mixture of a chiral cyclicsubstrate, e.g., prepared from an α- or β-heteroatom-substitutedcarboxylic acid, and a catalytic amount of non-racemic chiraltertiary-amine-containing catalyst. The cyclic substrate will includethe carboxylate carbon of the precursor α- or β-heteroatom-substitutedcarboxylic acid, which carboxylate carbon is susceptible to tandemattack by the tertiary-amine-containing catalyst and nucleophile. Thecombination is maintained under conditions appropriate for the chiraltertiary-amine-containing catalyst to catalyze the kinetic resolution ofthe racemic or diastereomeric mixture of the substrate. The methods canalso be applied to dynamic kinetic resolutions, e.g., wherein the yieldof the enantiomerically pure product from a kinetic resolution of aracemic substrate exceeds 50% due to in situ equilibration of theenantiomers of the substrate prior to attack of the catalyst at saidcarboxylate carbon. Dynamic kinetic resolution methods are preferred.

In the non-dynamic kinetic resolution methods, as applied to a racemicsubstrate, one enantiomer can be recovered as unreacted substrate whilethe other is transformed to the desired product. Of course, one ofordinary skill in the art will recognize that the desired product of akinetic resolution can be the enantiomer or diastereomer that reacts,the enantiomer or diastereomer that does not react, or both. Onesignificant advantage of the methods of the present invention is theability to use inexpensive racemic or diastereomeric mixtures of thestarting materials, rather than expensive, enantiomerically ordiastereomerically pure starting compounds.

The processes of this invention can provide optically active productswith very high stereoselectivity, e.g., enantioselectivity ordiastereoselectivity. In preferred embodiments of the subject kineticresolutions, the enantiomeric excess of the unreacted substrate orproduct or both is preferably greater than 50%, more preferably greaterthan 75% and most preferably greater than 90%. The processes of thisinvention can also be carried out under reaction conditions suitable forcommercial use, and typically proceed at reaction rates suitable forlarge-scale operations.

Further, the chiral products made available by the kinetic resolutionmethods of this invention can undergo further reaction(s) to afforddesired derivatives thereof. Such permissible derivatization reactionscan be carried out in accordance with conventional procedures known inthe art. For example, potential derivatization reactions includeesterification, N-alkylation of amides, and the like. The inventionexpressly contemplates the preparation of end-products and syntheticintermediates which are useful for the preparation or development orboth of pharmaceuticals, e.g., cardiovascular drugs, non-steroidalanti-inflammatory drugs, central nervous system agents, andantihistaminics.

In certain embodiments, the present invention relates to a method ofperforming a kinetic resolution of a racemic mixture or a diastereomericmixture of a chiral substrate, comprising the step of combining aracemic mixture or a diastereomeric mixture of a chiral substrate with anucleophile, in the presence of a chiral non-racemic catalyst, whereinsaid chiral non-racemic catalyst catalyzes the addition of saidnucleophile to said chiral substrate to give a chiral product orunreacted chiral substrate or both enriched in one enantiomer ordiastereomer.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidkinetic resolution is dynamic.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidnucleophile is an alcohol, amine or thiol.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidchiral non-racemic catalyst is a tertiary amine, phosphine or arsine.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidchiral non-racemic catalyst is a tertiary amine.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidchiral non-racemic catalyst is a cinchona alkaloid.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidchiral non-racemic catalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL,(DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB,DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidsubstrate comprises a single asymmetric carbon.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidnucleophile is an alcohol, amine or thiol; said chiral non-racemiccatalyst is a tertiary amine, phosphine or arsine; and said substratecomprises a single asymmetric carbon.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidnucleophile is an alcohol, amine or thiol; said chiral non-racemiccatalyst is a tertiary amine; and said substrate comprises a singleasymmetric carbon.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidnucleophile is an alcohol, amine or thiol; said chiral non-racemiccatalyst is a cinchona alkaloid; and said substrate comprises a singleasymmetric carbon.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein saidnucleophile is an alcohol, amine or thiol; said chiral non-racemiccatalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR,(DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN,DHQD-AQN, DHQ-PHN, or DHQD-PHN; and said substrate comprises a singleasymmetric carbon.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein theenantiomeric or diastereomeric excess of the product or unreactedsubstrate is greater than about 50%.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein theenantiomeric or diastereomeric excess of the product or unreactedsubstrate is greater than about 70%.

In certain embodiments, the present invention relates to theaforementioned method of performing a kinetic resolution, wherein theenantiomeric or diastereomeric excess of the product or unreactedsubstrate is greater than about 90%.

In certain embodiments, the present invention relates to a method ofkinetic resolution represented by Scheme 1:

wherein

X represents NR′, O, or S;

Y represents independently for each occurrence O or S;

Z represents NR′, O, or S;

R represents independently for each occurrence hydrogen, or optionallysubstituted alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R′ represents independently for each occurrence R, formyl, acyl,sulfonyl, —CO₂R, or —C(O)NR₂;

the substrate and the product are chiral;

NuH represents water, an alcohol, a thiol, an amine, a β-keto ester, amalonate, or the conjugate base of any of them;

chiral non-racemic catalyst is a chiral non-racemic tertiary amine,phosphine, or arsine;

n is 1 or 2; and

when said method is completed or interrupted, the enantiomeric excess ordiastereomeric excess of the unreacted substrate is greater than that ofthe substrate prior to the kinetic resolution, the enantiomeric excessor diastereomeric excess of the product is greater than zero, or both.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein Y is O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein NuH represents an alcohol, a thiol, or an amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein NuH represents an alcohol.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein said chiral non-racemic catalyst is a chiral non-racemictertiary amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein said chiral non-racemic catalyst is a cinchona alkaloid.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein said chiral non-racemic catalyst is quinidine, (DHQ)₂PHAL,(DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB,DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; and Y is O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; and NuH represents an alcohol, a thiol, or anamine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; and NuH represents an alcohol.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; and said chiral non-racemic catalyst is a chiralnon-racemic tertiary amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; and said chiral non-racemic catalyst is acinchona alkaloid.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; and said chiral non-racemic catalyst isquinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN,(DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN,DHQ-PHN, or DHQD-PHN.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; NuH represents an alcohol; and said chiralnon-racemic catalyst is a chiral non-racemic tertiary amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; NuH represents an alcohol; and said chiralnon-racemic catalyst is a cinchona alkaloid.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein X is O; Y is O; NuH represents an alcohol; and said chiralnon-racemic catalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR,(DHQD)₂PYR, (DHQD)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ,DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 50%.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 70%.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 1 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 90%.

In certain embodiments, the present invention relates to a method ofkinetic resolution represented by Scheme 2:

wherein

X represents NR′, O, or S;

Z represents NR′, O, or S;

R and R2 represent independently for each occurrence hydrogen, oroptionally substituted alkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; provided that R and R2 are not the same;

R′ represents independently for each occurrence R, formyl, acyl,sulfonyl, —CO₂R, or —C(O)NR₂;

chiral non-racemic catalyst is a chiral non-racemic tertiary amine,phosphine, or arsine; and

when said method is completed or interrupted, the enantiomeric excess ordiastereomeric excess of the unreacted substrate is greater than that ofthe substrate prior to the kinetic resolution, the enantiomeric excessor diastereomeric excess of the product is greater than zero, or both.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein X represents O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein Z represents NR′ or O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein said chiral non-racemic catalyst is a chiral non-racemictertiary amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein said chiral non-racemic catalyst is a cinchona alkaloid.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein said chiral non-racemic catalyst is quinidine, (DHQ)₂PHAL,(DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB,DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein X represents O; and Z represents NR′ or O.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein X represents O; Z represents NR′ or O; and said chiralnon-racemic catalyst is a chiral non-racemic tertiary amine.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein X represents O; Z represents NR′ or O; and said chiralnon-racemic catalyst is a cinchona alkaloid.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein X represents O; Z represents NR′ or O; and said chiralnon-racemic catalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR,(DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ,DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 50%.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 70%.

In certain embodiments, the kinetic resolution method of the presentinvention is represented by Scheme 2 and the attendant definitions,wherein the enantiomeric or diastereomeric excess of the product orunreacted substrate is greater than about 90%.

Nucleophiles

Nucleophiles useful in the present invention may be determined by theskilled artisan according to several criteria. In general, a suitablenucleophile will have one or more of the following properties: 1) Itwill be capable of reaction with the substrate at the desiredelectrophilic site; 2) It will yield a useful product upon reaction withthe substrate; 3) It will not react with the substrate atfunctionalities other than the desired electrophilic site; 4) It willreact with the substrate at least partly through a mechanism catalyzedby the chiral catalyst; 5) It will not substantially undergo furtherundesired reaction after reacting with the substrate in the desiredsense; and 6) It will not substantially react with or degrade thecatalyst. It will be understood that while undesirable side reactions(such as catalyst degradation) may occur, the rates of such reactionscan be rendered slow—through the selection of appropriate reactants andconditions—in comparison with the rate of the desired reaction(s).

Nucleophiles which satisfy the above criteria can be chosen for eachsubstrate and will vary according to the substrate structure and thedesired product. Routine experimentation may be necessary to determinethe preferred nucleophile for a given transformation. For example, if anitrogen-containing nucleophile is desired, it may be selected fromammonia, phthalimide, hydrazine, an amine or the like. Similarly, oxygennucleophiles such as water, hydroxide, alcohols, alkoxides, siloxanes,carboxylates, or peroxides may be used to introduce oxygen; andmercaptans, thiolates, bisulfite, thiocyanate and the like may be usedto introduce a sulfur-containing moiety. Additional nucleophiles will beapparent to those of ordinary skill in the art.

For anionic nucleophiles, the counterion can be any of a variety ofconventional cations, including alkali metal cations, alkaline earthcations, and ammonium cations.

In certain embodiments, the nucleophile may be part of the substrate,thus resulting in an intramolecular reaction.

Substrates

As discussed above, a wide variety of racemic and diastereomericmixtures serve as substrates in the methods of the present invention.The choice of substrate will depend on factors such as the nucleophileto be employed and the desired product, and an appropriate substratewill be apparent to the skilled artisan. It will be understood that thesubstrate preferably will not contain any functionalities that interferewith kinetc resolution of the present invention. In general, anappropriate substrate will contain at least one reactive electrophilicmoiety at which a nucleophile may attack with the assistance of thecatalyst. The catalyzed, stereoselective transformation of oneenantiomer of a racemic mixture, or one diastereomer of a distereomericmixture, is the basis of the kinetic resolutions of the presentinvention.

Most of the substrates contemplated for use in the methods of thepresent invention contain at least one ring having three to seven atoms.Small rings are frequently strained, enhancing their reactivity.However, in some embodiments a cyclic substrate may not be strained, andmay have a larger electrophilic ring.

Examples of suitable cyclic substrates in the subject methods includecompounds 1-6, depicted below. In certain embodiments, the substratewill be a racemic mixture. In certain embodiments, the substrate will bea mixture of diastereomers.

Reaction Conditions

The asymmetric reactions of the present invention may be performed undera wide range of conditions, though it will be understood that thesolvents and temperature ranges recited herein are not limitative andonly correspond to a preferred mode of the process of the invention.

In general, it will be desirable that reactions are run using mildconditions that will not adversely effect the substrate, the catalyst,or the product. For example, the reaction temperature influences thespeed of the reaction, as well as the stability of the reactants,products, and catalyst. The reactions will usually be run attemperatures in the range of −78° C. to 100° C., more preferably in therange −20° C. to 50° C. and still more preferably in the range −20° C.to 25° C.

In general, the asymmetric synthesis reactions of the present inventionare carried out in a liquid reaction medium. The reactions may be runwithout addition of solvent, e.g., where the nucleophile is a liquid.Alternatively, the reactions may be run in an inert solvent, preferablyone in which the reaction ingredients, including the catalyst, aresubstantially soluble. Suitable solvents include ethers such as diethylether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether,tetrahydrofuran and the like; halogenated solvents such as chloroform,dichloromethane, dichloroethane, chlorobenzene, and the like; aliphaticor aromatic hydrocarbon solvents such as benzene, toluene, hexane,pentane and the like; esters and ketones such as ethyl acetate, acetone,and 2-butanone; polar aprotic solvents such as acetonitrile,dimethylsulfoxide, dimethylformamide and the like; or combinations oftwo or more solvents. Furthermore, in certain embodiments it may beadvantageous to employ a solvent that is not inert to the substrateunder the conditions employed, e.g., use of ethanol as a solvent whenethanol is the desired nucleophile. In embodiments where water andhydroxide are not preferred nucleophiles, the reactions can be conductedunder anhydrous conditions. In certain embodiments, ethereal solventsare preferred. In embodiments where water and hydroxide are preferrednucleophiles, the reactions are run in solvent mixtures comprising anappropriate amount of water and/or hydroxide.

The invention also contemplates reaction in a biphasic mixture ofsolvents, in an emulsion or suspension, or reaction in a lipid vesicleor bilayer. In certain embodiments, it may be preferred to perform thecatalyzed reactions in the solid phase.

In some preferred embodiments, the reaction may be carried out under anatmosphere of a reactive gas. For example, kinetic resolutions withcyanide as nucleophile may be performed under an atmosphere of HCN gas.The partial pressure of the reactive gas may be from 0.1 to 1000atmospheres, more preferably from 0.5 to 100 atm, and most preferablyfrom about 1 to about 10 atm.

In certain embodiments it is preferable to perform the reactions underan inert atmosphere of a gas such as nitrogen or argon.

The asymmetric synthesis methods of the present invention can beconducted in continuous, semi-continuous or batch fashion and mayinvolve a liquid recycle and/or gas recycle operation as desired. Theprocesses of this invention are preferably conducted in batch fashion.Likewise, the manner or order of addition of the reaction ingredients,catalyst and solvent are also not critical and may be accomplished inany conventional fashion.

The reaction can be conducted in a single reaction zone or in aplurality of reaction zones, in series or in parallel or it may beconducted batchwise or continuously in an elongated tubular zone orseries of such zones. The materials of construction employed should beinert to the starting materials during the reaction and the fabricationof the equipment should be able to withstand the reaction temperaturesand pressures. Means to introduce and/or adjust the quantity of startingmaterials or ingredients introduced batchwise or continuously into thereaction zone during the course of the reaction can be convenientlyutilized in the processes especially to maintain the desired molar ratioof the starting materials. The reaction steps may be effected by theincremental addition of one of the starting materials to the other.Also, the reaction steps can be combined by the joint addition of thestarting materials to the optically active metal-ligand complexcatalyst. When complete conversion is not desired or not obtainable, thestarting materials can be separated from the product and then recycledback into the reaction zone.

The processes may be conducted in glass lined, stainless steel orsimilar type reaction equipment. The reaction zone may be fitted withone or more internal and/or external heat exchanger(s) in order tocontrol undue temperature fluctuations, or to prevent any possible“runaway” reaction temperatures.

Furthermore, the chiral catalyst can be immobilized or incorporated intoa polymer or other insoluble matrix by, for example, covalently linkingit to the polymer or solid support through one or more of itssubstituents. An immobilized catalyst may be easily recovered after thereaction, for instance, by filtration or centrifugation.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples that are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

EXAMPLE 1

Dynamic Kinetic Resolution of 5-Phenyl-1,3-dioxolane-2,4-dione Using(DHQD)₂AQN

A solution of 5-phenyl-1,3-dioxolane-2,4-dione (17.8 mg, 0.1 mmol) and(DHQD)₂AQN (18.2 mg, 0.02 mmol) in anhydrous diethyl ether (4 mL) wastreated with absolute EtOH (9 μL) at −78° C. The resulting reactionmixture was stirred for 8 hours at this temperature. The reaction wasthen quenched with HCl (0.2 N, 5 mL). The organic phase was separated,and the aqueous phase was extracted with diethyl ether (2×2.0 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, Hexane/Ethyl Acetate=2:1) to afford the mandelic ethylester as a colorless oil (12 mg, 67% yield). The enantiomeric excess ofthe mandelic ethyl ester was determined to be 97% by chiral HPLCanalysis.

EXAMPLE 2

Dynamic Kinetic Resolution of 5-Phenyl-1,3-dioxolane-2,4-dione UsingQuinidine

A solution of 5-phenyl-1,3-dioxolane-2,4-dione (17.8 mg, 0.1 mmol) andquinidine (6.5 mg, 0.02 mmol, 97% pure) with 10 mg dry 4 angstrommolecule sieves was treated with EtOH (9 μL) in one portion at −78° C.,then the reaction mixture was stirred for 8 hours at this temperature.The reaction was quenched with a large excess of methanol. Theconversion was determined to be 52% by GC. The enantiomeric excess ofthe product was determined to be 85% via chiral HPLC.

EXAMPLE 3

Kinetic Resolution of Racemic 5-Benzyl-1-aza-3-oxolane-2,4-dione Using(DHQD)₂AQN

To a solution of racemic Phenylalanine UNCA (15.3 mg, 0.047 mmol) and(DHQD)₂AQN (7.7 mg, 0.009 mmol) in dry diethyl ether (3.5 mL) at −60° C.was added dry methanol (0.25 mmol) in one portion. The resulting clearsolution was stirred at −60° C. for 5.5 hours. The reaction mixture wasquenched with HCl (2 N, 2.0 mL). The organic phase was separated, andthe aqueous phase was extracted with ether (2×1.0 mL). The combinedorganic layers were washed with HCl (2 N, 2×1.0 mL), followed by NaOH (2N, 1×3.0 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo togive the amino ester as a colorless oil (7.0 mg, 47% yield). The basicaqueous phase was acidified to pH<3 with concentrated HCl, and extractedwith ether (2×10 mL). The combined organics were dried over anhydrousNa₂SO₄, and concentrated in vacuo to give the amino acid (5.2 mg, 37%yield). The enantiomeric excess of the amino ester and the amino acidwere determined to be 93% and 94%, respectively, by HPLC analysis.

EXAMPLE 4

Kinetic Resolution of Racemic 5-Benzyl-1-aza-3-oxolane-2,4-dione UsingQuinidine

To a mixture of UNCA (Phe-Z) (16.3 mg, 0.05 mmol), (+)-quinidine (3.2mg, 0.01 mmol) and 4 Å molecular sieves (10 mg), anhydrous ether (3.5mL) was added, the resulting mixture was stirred at room temperature for15 minutes, then cooled to −60° C. and methanol solution in ether (5%v/v), 21.1 μL, 0.026 mmol of methanol) was introduced. The resultingreaction mixture was stirred at −60° C. for 40 h. A small amount ofreaction mixture (50 μL) was added to dry ethanol (200 μL) and theresulting solution was stirred at room temperature for 30 min., thenpassed through a silica gel plug with ether as the eluent. The solventwas removed under reduced pressure to give a mixture of methyl and ethylesters for GC (HP-5 column, 200° C., 4 min., raised to 250° C. at 10°C./min and 250° C., 8 min) and chiral HPLC (Daicel chiralpak OJ column,4:1, Hexanes:IPA, 0.7 mL/min, λ=220 nm) analysis. The conversion of thestarting material was 43.8%, the enantiomeric excess of the product was85.6%, and the enantiomeric excess of the starting material was 69.2%,as reflected by the ethyl ester. Based on these numbers, the selectivefactor (s=k_(fast)/k_(slow)) was calculated to be larger than 20.

EXAMPLE 5

General Procedure for the Preparation of Dioxolanediones

Mandelic acid (0.5 g) was dissolved in 5 mL dry THF, and treated withdiphosgene (0.8 ml), then added catalytic amount of activated charcoal(about 10 mg). The mixture was stirred at room temperature overnight,and filtered through Celite. The solvent was removed under vacuum togive the product in roughly quantitative yield (>95%).

EXAMPLE 6

Preparation of α-Amino Acid N-Carboxy Anhydrides (NCAs and UNCAs)

General Procedures

A. NCAs

To a suspension of the racemic acid (3.0-25.0 mmol) in anhydrous THF(8-40 mL) at 50° C. was added triphosgene (1.0 eq.) in one portion. If aclear solution has not formed within one hour, 1-2 aliqouts oftriphosgene (0.1 eq/aliquot) were added to the reaction mixture at 45min intervals. The reaction mixture was stirred at 50° C. for a total of3 h, afterwhich the insoluble material (if there is any) in the reactionmixture was removed by filtration. The filtrate was poured into hexanes(20-120 mL) and the resulting mixture was stored in a freezer (−20° C.)overnight. The white crystals formed during this time were collected anddried under vacuum to give the desired NCAs, which were used for thenext step without further purification.

B. UNCAs

To a solution of the racemic NCA (1.0-10.0 mmol) in dry THF (5.0-25.0mL) at −25° C., alkyl (benzyl, allyl and fluorenylmethyl) chloroformate(1.2-1.3 eq.) was added. A solution of N-methyl-morpholine (NMM)(1.25-1.5 eq.) in THF (1.0-5.0 mL) was introduced dropwise to thereaction mixture over a period of 15 min. The resulting mixture wasstirred at −25° C. for 1 h, then allowed to warm to room temperatureovernight. The reaction mixture was cooled to −25° C. and acidified byHCl (4.0 M in Dioxane) until the pH of the mixture is approximately 3.The resulting mixture was allowed to warm to room temperature. Theprecipitation (NMM hydrochloride) was removed by filtration under N₂atmosphere with the aid of dry Celite 521 (3.0 g) and washed with dryTHF (2×20 mL). The filtrate was concentrated and the residue wassubjected to recrystallization from TBME/THF/hexanes at −20° C.overnight. The white solid was collected and dried under vacuum to givethe desired UNCAs in yields ranging from 47 to 86% (average yield for 14UNCAs listed in Table 3 is 67%) from racemic amino acid.

Specific Compounds Prepared

This product was obtained in 72% yield from the corresponding racemicamino acid. m.p. 105-106° C.; ¹H NMR (400 MHz, CDCl₃) δ 3.28 (dd, J=14.0and 2.4 Hz, 1H), 3.47 (dd, J=14.0 and 5.5 Hz, 1H), 4.93 (dd, J=5.5 and2.4 Hz, 1H), 5.40 (s, 1H), 6.88-6.90 (m, 2H), 7.21-7.26 (m, 3H),7.41-7.47 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 35.06, 60.98, 69.77,128.22, 128.71, 128.83, 129.10, 129.13, 129.35, 131.92, 134.10, 145.52,149.18, 165.37.

This product was obtained 79% yield from the corresponding racemic aminoacid. ¹H NMR (400 MHz, CDCl₃) δ 3.23-3.30 (m, 1H), 3.41-3.49 (m, 1H),4.89-4.96 (m, 1H), 5.04 (s, 2H), 6.81-6.93 (m, 4H), 7.41-7.48 (m, 5H);¹³C NMR (100 MHz, CDCl₃) δ 34.45, 61.09, 70.10, 116.36 (d, J=21.2 Hz),127.91, 129.01, 129.07, 129.40, 131.30, 134.27, 145.64, 149.41, 161.73(d, J=246 Hz), 165.50; IR (CHCl₃) γ 1874, 1809, 1743, 1511, 1456 cm⁻¹;HRMS (DCI) exact mass calcd for (C₁₈H₁₄NO₅F+NH₄ ⁺) requires m/z361.1200, found m/z 361.1212.

This product was obtained in 47% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.26 (dd, J=14.3 and 2.2 Hz, 1H),3.44 (dd, J=14.3 and 5.8 Hz, 1H), 4.93 (dd, J=2.2 and 5.8 Hz, 1H), 5.40(s, 1H), 6.81 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.40-7.50 (m,5H); ¹³C NMR (100 MHz, CDCl₃) δ 34.37, 60.69, 69.90, 128.79, 128.86,129.20, 129.34, 130.44, 130.69, 134.01, 134.31, 145.37, 149.17, 165.18;IR (CHCl₃) γ 1874, 1809, 1743, 1493, 1456, 1362, 1264, 1015, 960 cm⁻¹;HRMS (DCI) exact mass calcd for (C₁₈H₁₄ClNO₅+NH₄ ⁺) requires m/z377.0904, found m/z 377.0921.

This product was obtained in 77% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.20-3.26 (m, 1H), 3.37-3.45 (m,1H), 4.88-4.95 (m, 1H), 5.39 (s, 2H), 6.74 (d, J=8.2 Hz, 2H), 7.32 (d,J=8.2 Hz, 2H), 7.39-7.47 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 34.66,60.87, 70.15, 122.63, 128.99, 129.06, 129.39, 131.21, 132.48, 134.20,145.59, 149.33, 165.38; IR (CHCl₃) γ 1873, 1809, 1744, 1489, 1456 cm⁻¹;HRMS (DCI) exact mass calcd for (C₁₈H₁₄NO₅Br+NH₄ ⁺) requires m/z421.0399, found m/z 421.0386.

This product was obtained in 62% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.52-3.57 (m, 1H), 3.73-3.78 (m,1H), 4.91-4.93 (m, 1H), 5.40 (d, J=12.0 Hz, 1H), 5.44 (d, J=12.0 Hz,1H), 6.68-6.69 (m, 1H), 6.90-6.92 (m, 1H), 7.19-7.20 (m, 1H), 7.38-7.49(m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 29.43, 60.93, 69.91, 126.29, 127.71,128.12, 128.73, 128.90, 129.12, 132.83, 134.17, 145.83, 149.10, 165.41;IR (CHCl₃) γ 1874, 1808, 1739, 1519, 1456 cm⁻¹; HRMS (DCI) exact masscalcd for (C₁₆H₁₃NO₅S+NH₄ ⁺) requires m/z 349.0858, found m/z 349.0844.

This product was obtained in 54% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 0.84 (t, J=7.0 Hz, 3H), 1.15-1.36(m, 8H), 1.95-2.18 (m, 2H), 4.71 (dd, J=6.7 and 3.1 Hz, 1H), 5.29 (d,J=11.9 Hz, 1H), 5.38 (d, J=11.9 Hz, 1H), 7.30-7.42 (m, 5H); ¹³C NMR (100MHz, CDCl₃) δ 13.89, 22.33, 23.01, 28.44, 29.72, 31.22, 59.94, 69.64,128.39, 128.77, 128.96, 134.02, 146.21, 148.97, 165.88; IR (CHCl₃) γ2930, 2858, 1871, 1812, 1742, 1498, 1456, 1387, 1304 cm⁻¹; HRMS (DCI)exact mass calcd for (C₁₇H₂₁NO₅+NH₄ ⁺) requires m/z 337.1763, found m/z337.1758.

This product was obtained in 61% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.83-3.89 (m, 1H), 3.97-4.03 (m,1H), 4.44 (d, J=12.4 Hz, 1H), 4.51 (d, J=12.4 Hz, 1H), 4.64-4.70 (m,1H), 5.25 (s, 2H), 7.17-7.22 (m, 2H), 7.27-7.39 (m, 8H); ¹³C NMR (100MHz, CDCl₃) δ 61.14, 65.47, 69.81, 73.59, 127.87, 128.35, 128.54,128.78, 128.98, 129.13, 134.20, 136.72, 146.36, 149.10, 164.73; IR(CHCl₃) γ 1876 1808, 1745, 1496, 1454 cm⁻¹; HRMS (DCI) exact mass calcdfor (C₁₉H₁₇NO₆+NH₄ ⁺) requires m/z 373.1400, found m/z 373.1409.

This product was obtained in 84% yield from the corresponding racemicamino acid. m.p. 79-81° C.; ¹H NMR (400 MHz, CDCl₃) δ 0.95 (d, J=7.3 Hz,3H), 1.20 (d, J=7.3 Hz, 3H), 2.50-2.62 (m, 1H), 4.61 (d, J=3.7 Hz, 1H),5.34 (d, J=12.2 Hz, 1H), 5.38 (d, J=12.2 Hz, 1H), 7.30-7.48 (m, 5H); ¹³CNMR (100 MHz, CDCl₃) δ 15.75, 17.92, 29.94, 64.98, 69.96, 128.51,129.02, 129.04, 129.18, 134.25, 146.50, 149.44, 164.48.

This product was obtained in 60% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 5.16 (d, J=11.9 Hz, 1H), 5.25 (d,J=11.9 Hz, 1H), 5.62 (s, 1H), 7.14-7.18 (m, 2H), 7.24-7.46 (m, 8H); ¹³CNMR (100 MHz, CDCl₃) δ 63.38, 69.80, 126.55, 128.30, 128.64, 128.86,129.52, 130.06, 131.48, 133.71, 146.10, 148.39, 163.73; IR (CHCl₃) γ1874, 1812, 1746, 1498, 1456, 1354, 1242, 1008 cm⁻¹; HRMS (DCI) exactmass calcd for (C₁₇H₁₃NO₅+NH₄ ⁺) requires m/z 329.1137, found m/z329.1125.

This product was obtained in 86% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.81 (s, 3H), 5.14 (d, J=12.0 Hz,1H), 5.23 (d, J=12.0 Hz, 1H), 5.55 (s, 1H), 6.87-6.90 (m, 2H), 7.14-7.22(m, 4H), 7.27-7.32 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 55.58, 63.20,69.83, 115.02, 123.65, 128.37, 128.49, 128.78, 128.97, 134.02, 146.43,148.65, 160.97, 164.46; IR (CHCl₃) γ 1873, 1814, 1749, 1611, 1586, 1515,1455 cm⁻¹; HRMS (DCI) exact mass calcd for (C₁₈H₁₅NO₆+NH₄ ⁺) requiresm/z 359.1243, found m/z 359.1227.

This product was obtained in 73% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.00-3.16 (m, 2H), 4.34 (t, J=6.1Hz, 1H), 4.68 (dd, J=5.5 and 3.1 Hz, 1H), 4.72-4.84 (m, 2H), 6.80-6.90(m, 2H), 7.20-7.32 (m, 3H), 7.32-7.40 (m, 2H), 7.40-7.40 (m, 2H), 7.64(d, J=7.3 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.74-7.84 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 34.74, 46.47, 60.87, 69.56, 120.16, 120.23, 124.91,124.98, 127.42, 127.49, 128.18, 128.23, 129.12, 129.34, 131.85, 141.33,141.39, 142.71, 142.77, 145.54, 149.05, 165.25.

D,L-phenylalanine NCA (1.615 g, 8.45 mmol) was dissolved in THF (23 mL).The solution was then cooled to −15° C. with stirring and Boc₂O (2.40 g,11.0 mmol), pyridine (1.38 mL, 17.0 mmol) and flamed-dried powdered 4 Åmolecular sieves (0.2 g) were added successively. The flask was sealedand stored in a freezer at −15° C. for 6 days. For other procedure, seethe typical prodedure. This product was obtained in 63% yield from thecorresponding racemic amino acid. m.p. 101-103° C.; ¹H NMR (400 MHz,CDCl₃) δ 1.62 (s, 9H), 3.33 (dd, J=14.3 and 2.5 Hz, 1H), 3.52 (dd, 14.3and 5.6 Hz, 1H), 4.91 (dd, J=5.6 and 2.5 Hz, 1H), 7.05-7.12 (m, 2H),7.29-7.37 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 27.92, 35.27, 60.75,86.02, 128.24, 129.13, 129.43, 132.26, 145.76, 147.62, 165.78.

This product was obtained in 61% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ 3.35 (dd, J=14.2 and 2.4 Hz, 1H),3.55 (dd, 14.2 and 5.6 Hz, 1H), 4.83-4.92 (m, 2H), 4.98 (dd, 5.6 and 2.4Hz, 1H), 5.37-5.55 (m, 2H), 5.95-6.06 (m, 1H), 7.00-7.12 (m, 2H),7.22-7.40 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 35.16, 60.93, 68.66,120.51, 128.34, 129.21, 129.44, 130.24, 132.02, 145.51, 149.16, 165.34;IR (CHCl₃) γ 3032, 1872, 1808, 1743, 1497, 1455, 1374, 1266 cm⁻¹; HRMS(DCI) exact mass calcd for (C₁₄H₁₃NO₅+NH₄ ⁺) requires m/z 293.1137,found m/z 193.1147.

This product was obtained in 64% yield from the corresponding racemicamino acid. ¹H NMR (400 MHz, CDCl₃) δ2.42-2.55 (m, 2H), 2.67-2.84 (m,2H), 4.70-4.82 (m, 3H), 5.32-5.40 (m, 1H), 5.40-5.50 (m, 1H), 7.14-7.38(m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 29.74, 30.98, 59.31, 68.62, 120.63,126.79, 128.32, 128.77, 130.16, 138.67, 145.91, 148.87, 165.63; IR(CHCl₃) γ 3028, 2940, 1870, 1808, 1743, 1497, 1455, 1376, 1307 cm⁻¹.

EXAMPLE 7

General Method for the Kinetic Resolution of Urethane-Protected α-AminoAcid N-Carboxy Anhydrides (UNCAs)

A mixture of an UNCA 2 (0.10 mmol) and 4 Å molecular sieves (10 mg) inanhydrous diethyl ether (7.0 mL) was stirred at room temperature for 15minutes, then cooled to the temperature indicated in Table 3, afterwhichthe modified cinchona alkaloid (0.01 mmol) was added to the mixture. Theresulting mixture was stirred for another 5 minutes and then a solutionof methanol in ether (v/v=1/19, 0.052-0.10 mmol of methanol, in entry 9and 10, 0.055 mmol of ethanol was used) was introduced dropwise via asyringe. The resulting reaction mixture was stirred at that temperaturefor 15-85 h. The reaction was quenched by HCl in ether (1 N, 1.0 mL).After 15 minutes, aq. HCl (2 N, 2.0 mL) was added to the reactionmixture, and the resulting mixture was allowed to warm to roomtemperature. The organic phase was collected, washed with aq.HCl (2 N,2×1 mL), dried (Na₂SO₄), and concentrated. The residue was dissolved inH₂O/THF (v/v: 1/4, 5.0 mL) and the resulting solution was stirred atroom temperature overnight. The solution was then concentrated and theresidue was dissolved in ether (3.0 mL). The resulting resolution wasextracted with aq. Na₂CO₃ (1 N, 2×3.0 mL). The organic layer was washedwith water (1.0 mL), dried (Na₂SO₄), and concentrated to give aminoesters 3 in NMR-pure form and in yields indicated in Table 3. Theaqueous phases were combined and then acidified with conc. HCl tillpH<3, then extracted with ethyl acetate (3×10 mL). The organic phase wasdried (Na₂SO₄), and concentrated to give amino acids 4 in NMR-pure formand in yields indicated in Table 3. This procedure described above isused for the kinetic resolution of 2a-d, f-i, k-n.

For kinetic resolutions of 2e and 2j, chromatographic purification wasused for the isolation of amino esters 3e, 3j and amino acids 4e, 4j asfollowing: After the reaction was quenched and the catalyst wasconverted to the corresponding ammonium salt with aq. HCl as describedabove, the residue obtained from concentration of the organic phase(instead of being subjected to exhaustive hydrolysis in H₂O/THF) wassubjected to flash chromatography (SiO₂) with first ether/hexanes(v/v=1/5) as eluent to give the desired esters 3 (e, j) and thenether/AcOH (v/v=100/1) as eluent to give the desired amino acids 4 (e,j) in NMR-pure form and in yields indicated in Table 3.

EXAMPLE 8

General Method for Determining the Extent of Conversion of a KineticResolution of Urethane-Protected α-Amino Acid N-Carboxy Anhydrides(UNCAs)

A small aliquot (50 μL) of a reaction mixture was added to dry ethanol(200 μL). The resulting mixture was stirred at r.t. for 30 min, then wasallow to pass through a plug of silica gel with ether. The solution wasconcentrated and then subjected to GC analysis (HP-5 column, 200° C., 4min., 10° C./min to 250° C., 250° C., 8-12 min). For kinetic resolutionsof UNCA 2i and 2j using ethanol as the nucleophile (entries 9 and 10,Table 3), the aliquot of the reaction mixture was added to dry methanol.The experimentally-determined conversions and the calculatedconversions, as indicated below, are consistent with each other.

EXAMPLE 9

General Procedure for Determining the Enantiomeric Excesses of theProducts and Unreacted Starting Materials of the Kinetic Resolutions

The enantiomeric excesses of esters 3 were determined by HPLC analysesfollowing conditions specified below. The enantiomeric excesses of theunreacted UNCAs 2 were determined by converting 2 to esters 5 asdescribed above and measuring enantiomeric excesses of ester 5 by HPLCanalyses following conditions specified below. The enantiomeric excessesof amino acids 4 were determined by HPLC analyses and were found to be,without exception, consistent with the enantiomeric excesses of thecorresponding esters 5.

(S)-(N-Benzyloxycarbonyl)phenylalanine (4a)

In a large scale (4 mmol) reaction, this product was obtained as a whitesolid in 48% isolated yield and 97% ee (as a ethyl ester) as determinedby chiral HPLC analysis [Daicel chiralpak OJ column, Hexanes:IPA, 80:20,0.7 mL/min, λ 220 nm, t(major, ethyl ester)=18.47 min, t(minor, ethylester)=21.42 min], m.p. [α]_(D)=+4.8 (c 2.21, AcOH); (Literature,[α]_(D)=+5.1 (c 2.0, AcOH), for S-enantiomer); ¹H NMR (400 MHz, CDCl₃,4.7:1 mixture of rotamers) δ 3.02-3.24 (m, 2H), 3.62-3.74 (m, 1H), 5.10(s, 2H), 5.17 (d, J=7.9 Hz, 1H), 7.10-7.38 (m, 10H); ¹H NMR (minorrotamer, partial) δ 2.92-3.04 (m, 2H), 4.50-4.60 (m, 1H), 4.90-5.04 (m,2H), 5.70-5.80 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 37.70, 54.52, 67.16,127.28, 128.11, 128.26, 128.54, 128.71, 129.31, 135.38, 136.02, 155.84,175.89.

(R)-Methyl-(N-Benzyloxycarbonyl)phenylalaninate (3a)

This product was obtained as a colorless oil in 48% isolated yield and93% ee as determined by chiral HPLC analysis [Daicel chiralpak OJcolumn, Hexanes:IPA, 80:20, 0.7 mL/min, λ 220 nm, t(minor)=24.78 min,t(major)=37.56 min]. [α]_(D)=+13.9 (c 1.60, MeOH); (Literature, [α]_(D)¹⁹ =−15.6 (c 1.02, MeOH), for S-enantiomer); ¹H NMR (400 MHz, CDCl₃,5.5:1 mixture of rotamers) δ 3.02-3.18 (m, 2H), 3.72 (s, 3H), 4.68 (dd,J=14.0 and 6.1 Hz, 1H), 5.02-5.14 (m, 2H), 5.21 (br d, J=7.9 Hz, 1H),7.02-7.14 (m, 2H), 7.20-7.40 (m, 8H), ¹H NMR (minor rotamer, partial) δ2.92-3.04 (m, 2H), 3.66 (s, 3H), 4.48-4.58 (m, 1H), 4.92-5.02 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ 38.22, 52.28, 54.78, 66.95, 127.13, 128.06,128.17, 128.50, 128.59, 129.24, 135.66, 136.24, 155.60, 171.94.

Ethyl (N-Benzyloxycarbonyl)phenylalaninate (5a):

¹H NMR (400 MHz, CDCl₃, 5.6:1 mixture of rotamers) δ 1.22 (t, J=7.3 Hz,3H), 3.04-3.18 (m, 2H), 4.16 (q, J=7.3 Hz, 2H), 4.64 (dd, J=14.0 and 6.1Hz, 1H), 5.10 (s, 2H), 5.25 (d, J=7.9 Hz, 1H), 7.06-7.14 (m, 2H),7.18-7.40 (m, 8H); ¹H NMR (minor rotamer, partial) δ 2.92-3.04 (m, 1H),4.46-4.56 (m, 1H), 4.98-5.06 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 14.05,38.27, 54.81, 61.46, 66.90, 127.06, 128.05, 128.14, 128.49, 128.52,129.31, 135.74, 136.26, 155.58, 171.46.

(S)-(N-Benzyloxycarbonyl)-p-fluorophenylalanine (4b)

This product was obtained as a white solid in 42% isolated yield and 92%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD column, Hexanes:IPA, 95:5, 1.0 mL/min, λ 220 nm, t(minor,ethyl ester)=25.98 min, t(major, ethyl ester)=17.47 min] from a reactioncatalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55 eq. ofmethanol and was stirred at −78° C. for 31 h when the reactionconversion reached 50%. [α]_(D)=+(c 0.92, EtOH); ¹H NMR (400 MHz,CDCl_(3,) 3.0:1 mixture of rotamers) δ 3.00-3.08 (m, 1H), 3.10-3.21 (m,1H), 4.62-4.70 (m, 1H), 5.06 (d, J=12.0 Hz, 1H), 5.12 (d, J=12.0 Hz,1H), 5.23-5.28 (m, 1H), 6.90-6.99 (m, 2H), 7.01-7.12 (m, 2H), 7.28-7.39(m, 5H), 8.60 (s, br., 1H); ¹H NMR (minor rotamer, partial) δ 2.85-2.94(m, 1H), 3.04-3.14 (m, 1H), 4.44-4.52 (m, 1H), 6.26-6.32 (m, 1H); ¹³CNMR (100 MHz, CDCl₃) δ 37.18, 54.85, 67.43, 115.74 (d, J=21.3 Hz),128.44 (d, J=19.0 Hz), 128.77, 131.02, 131.10, 131.43, 136.19, 156.05,162.26 (d, J=244 Hz), 176.15.

(R)-Methyl-(N-Benzyloxycarbonyl)-p-fluorophenylalaninate (3b)

This product was obtained as a white solid in 48% isolated yield and 92%ee as determined by chiral HPLC analysis [Daicel chiralpak OD column,Hexanes:IPA, 95:5, 1.0 mL/min, λ 220 nm, t(major)=29.19 min,t(minor)=22.49 min]. [α]_(D)=−(c 1.21, CHCl₃); ¹H NMR (400 MHz,CDCl_(3,) 7.4:1 mixture of rotamers) δ 3.00-3.16 (m, 2H), 3.72 (s, 3H),4.60-4.68 (m, 1H), 5.07 (d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H),5.21-5.28 (m, 1H), 6.91-7.00 (m, 2H), 7.00-7.08 (m, 2H), 7.29-7.40 (m,5H); ¹H NMR (minor rotamer, partial) δ 2.90-3.02 (m, 2H), 3.64-3.72 (m,3H), 4.46-4.55 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 37.66, 52.58, 55.01,67.21, 115.65 (d, J=21.0 Hz), 128.38 (d, J=12.9 Hz), 128.74, 130.93,131.01, 131.65, 136.39, 155.76, 162.22 (d, J=244 Hz), 172.00.

Ethyl (N-Benzyloxycarbonyl)-p-fluorophenylalaninate (5b)

¹H NMR (400 MHz, CDCl_(3,) 5.7:1 mixture of rotamers) δ 1.23 (t, J=7.0Hz, 3H), 3.00-3.15 (m, 2H), 4.08-4.21 (m, 2H), 4.57-4.65 (m, 1H), 5.07(d, J=12.0 Hz, 1H), 5.12 (d, J=12.0 Hz, 1H), 5.25-5.34 (m, 1H),6.91-7.00 (m, 2H), 7.00-7.08 (m, 2H), 7.29-7.40 (m, 5H); ¹H NMR (minorrotamer, partial) δ 2.90-3.02 (m, 2H), 4.45-4.53 (m, 1H); ¹³C NMR (100MHz, CDCl₃) δ 14.28, 37.70, 55.02, 61.75, 67.14, 115.55 (d, J=21.3 Hz),128.35 (d, J=11.4 Hz), 128.71, 130.98, 131.06, 131.71, 136.41, 155.74,162.18 (d, J=244 Hz), 171.52.

(S)-(N-Benzyloxycarbonyl)-p-chlorophenylalanine (4c)

This product was obtained as a white solid in 43% isolated yield and 97%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OJ column, Hexanes:IPA, 90:10, 1.0 mL/min, λ 220 nm, t(minor,ethyl ester)=21.10 min, t(major, ethyl ester)=24.92 min] from a reactioncatalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55 eq. ofmethanol and was stirred at −60° C. for 18 h when the reactionconversion reached 53%. [α]_(D)=+4.1 (c 0.92, EtOH); ¹H NMR (400 MHz,acetone-d6) δ 3.01 (dd, J=14.0 and 9.7 Hz, 1H), 3.23 (dd, J=14.0 and 4.9Hz, 1H), 4.44-4.54 (m, 1H), 5.00 (d, J=12.8 Hz, 1H), 5.04 (d, J=12.8 Hz,1H), 5.58 (d, J=8.5 Hz, 1H), 7.24-7.40 (m, 9H); ¹³C NMR (100 MHz,acetone-d6) δ 37.42, 55.95, 66.62, 128.49, 128.57, 129.11, 131.89,132.80, 137.35, 138.11, 156.81, 173.02; IR (KBr) γ 3324, 3036, 2936,1714, 1691, 1534, 1490, 1456, 1420, 1263, 1057 cm⁻¹; HRMS (DCI) exactmass calcd for (C₁₇Hl₇ClNO₄+NH₄ ⁺) requires m/z 334.0846, found m/z334.0856.

(R)-Methyl-(N-Benzyloxycarbonyl)-p-chlorophenylalaninate (3c)

This product was obtained as a white solid in 52% isolated yield and 88%ee as determined by chiral HPLC analysis [Daicel chiralpak OJ column,Hexanes:IPA, 90:10, 1.0 mL/min, λ 220 nm, t(major)=31.25 min,t(minor)=37.17 min]. [α]_(D)=−46.4 (c 1.21, CHCl₃); ¹H NMR (400 MHz,CDCl_(3,) 8.5:1 mixture of rotamers) δ 3.03 (dd, 14.0 and 6.1 Hz, 1H),3.12 (dd, J=14.0 and 5.5 Hz, 1H), 3.72 (s, 3H), 4.64 (m, 1H), 5.06 (d,J=12.2 Hz, 1H), 5.12 (d, J=12.2 Hz, 1H), 5.25 (d, J=7.9 Hz, 1H), 7.02(d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.26-7.40 (m, 5H); ¹H NMR(minor rotamer, partial) δ 2.88-2.98 (m, 2H), 3.67 (br s, 3H), 4.44-4.56(m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 37.59, 52.39, 54.63, 67.00, 128.08,128.23, 128.52, 128.70, 130.58, 133.02, 134.21, 136.13, 155.51, 171.67;IR (CHCl₃) γ 3345, 2956, 2930, 1731, 1715, 1520, 1494, 14371209, 1046cm⁻¹; HRMS (DCI) exact mass calcd for (C₁₈H₁₉ClNO₄+NH₄ ⁺) requires m/z348.1003, found m/z 348.1006.

Ethyl (N-Benzyloxycarbonyl)-p-chlorophenylalaninate (5c)

¹H NMR (400 MHz, CDCl_(3,) 6.2:1 mixture of rotamers) δ 1.23 (t, J=7.3Hz, 3H), 3.03 (dd, J=13.7 and 6.1 Hz, 1H), 3.12 (dd, J=13.7 and 5.8 Hz,1H), 4.16 (q, J=7.3 Hz, 2H), 4.56-4.66 (m, 1H), 5.07 (d, J=12.2 Hz, 1H),5.12 (d, J=12.2 Hz, 1H), 5.28 (d, J=7.9 Hz, 1H), 7.03 (d, J=8.5 Hz, 2H),7.18-7.40 (m, 7H); ¹H NMR (minor rotamer, partial) δ 2.88-2.98 (m, 2H),4.42-4.52 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.08, 37.64, 54.65,61.61, 66.96, 128.08, 128.21, 128.63, 130.66, 132.96, 134.29, 136.17,155.51, 171.20.

(S)-(N-Benzyloxycarbonyl)-p-bromophenylalanine (4d)

This product was obtained as a white solid in 39% isolated yield and 97%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OJ column, Hexanes:IPA, 80:20, 0.7 mL/min, λ 220 nm, t(minor,ethyl ester)=20.06 min, t(major, ethyl ester)=24.19 min] from a reactioncatalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55 eq. ofmethanol and was stirred at −78° C. for 45 h when the reactionconversion reached 53%. [α]_(D)=+(c 0.92, EtOH); ¹H NMR (400 MHz,DMSO-d₆) δ 2.75-2.83 (m, 1H), 2.98-3.07 (m, 1H), 3.34 (s, br., 1H),4.13-4.20 (m, 1H), 4.96 (s, 2H), 7.19-7.36 (m, 6H), 7.45 (d, J=8.0 Hz,2H), 7.67 (d, J=8.8 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 35.84, 55.24,65.24, 119.59, 127.46, 127.71, 128.28, 131.00, 131.40, 136.99, 137.36,155.97, 173.10.

(R)-Methyl-(N-Benzyloxycarbonyl)-p-chlorophenylalaninate (3d)

This product was obtained as a white solid in 51% isolated yield and 87%ee as determined by chiral HPLC analysis [Daicel chiralpak OJ column,Hexanes:IPA, 80:20, 0.7 mL/min, λ 220 nm, t(major)=27.90 min,t(minor)=34.17 min]. [α]_(D)=−(c 1.21, CHCl₃); ¹H NMR (400 MHz,CDCl_(3,) 6.8:1 mixture of rotamers) δ 3.00 (dd, J=13.6 and 2.2 Hz, 1H),3.11 (dd, J=13.6 and 1.2 Hz, 1H), 3.71 (s, 3H), 4.60-4.68 (m, 1H), 5.06(d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.26-5.32 (m, 1H), 6.95 (d,J=8.0 Hz, 2H), 7.29-7.40 (m, 7H); ¹H NMR (minor rotamer, partial) δ2.91-3.00 (m, 2H), 3.64-3.72 (m, 3H), 4.46-4.55 (m, 1H); ¹³C NMR (100MHz, CDCl₃) δ 37.83, 52.61, 54.78, 67.20, 121.31, 128.28, 128.42,128.72, 131.15, 131.85, 134.94, 136.33, 155.72, 171.86.

Ethyl (N-Benzyloxycarbonyl)-p-chlorophenylalaninate (5d)

¹H NMR (400 MHz, CDCl_(3,) 5.5:1 mixture of rotamers) δ 1.23 (t, J=7.0Hz, 3H), 3.01 (dd, J=14.0 and 2.2 Hz, 1H), 3.10 (dd, J=14.0 and 1.8 Hz,1H), 4.16 (q, J=7.2 Hz, 2H), 4.58-4.66 (m, 1H), 5.06 (d, J=12.0 Hz, 1H),5.11 (d, J=12.0 Hz, 1H), 5.25-5.31 (m, 1H), 6.97 (d, J=7.6 Hz, 2H),7.30-7.42 (m, 7H); ¹H NMR (minor rotamer, partial) δ 2.88-2.96 (m, 2H),4.45-4.52 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.31, 37.92, 54.81,61.84, 67.18, 121.28, 128.30, 128.43, 128.73, 131.24, 131.80, 135.04,136.38, 155.72, 171.40; IR (CHCl₃) γ 3338, 1732, 1715, 1592, 1515, 1455cm⁻¹; HRMS (DCI) exact mass calcd for (C₁₉H₂₀NO₄Br+NH₄ ⁺) requires m/z406.0654, found m/z 406.0653.

(S)-(N-Benzyloxycarbonyl)-3-(2-thienyl)alanine (4e)

This product was obtained as a white solid in 45% isolated yield and 94%ee (as an ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD column, Hexanes:IPA, 92.3:7.7, 0.8 mL/min, λ 220 nm,t(minor, ethyl ester)=23.12 min, t(major, ethyl ester)=16.42 min] from areaction catalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55eq. of methanol and was stirred at −78° C. for 25 h when the reactionconversion reached 50%. [α]_(D)=+48 (c 0.85, CHCl₃); Lit. (S, 99.8% ee)[α]_(D)=+54 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl_(3,) 7.1:1 mixture ofrotamers) δ 3.35-3.42 (m, 2H), 4.68-4.72 (m, 1H), 5.11 (m, 2H),5.44-5.48 (m, 1H), 6.79-6.81 (m, 1H), 6.85-6.91 (m, 1H), 7.10-7.15 (m,1H), 7.29-7.37 (m, 5H), 10.69 (s, br., 1H); ¹H NMR (minor rotamer,partial) δ 3.18-3.26 (m, 1H), 3.30-3.38 (m, 1H), 4.47-4.55 (m, 1H),6.38-6.44 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 32.16, 54.66, 67.45,125.19, 127.14, 127.26, 128.28, 128.43, 128.71, 136.99, 156.09, 175.84.

(R)-Methyl-(N-Benzyloxycarbonyl)-3-(2-thienyl)alaninate (3e)

This product was obtained as a colorless oil in 49% isolated yield and94% ee as determined by chiral HPLC analysis [Daicel chiralpak OJcolumn, Hexanes:IPA, 90:10, 1.0 mL/min, λ 220 nm, t(major)=25.94 min,t(minor)=20.23 min]. [α]_(D)=−49 (c 1.30, CHCl₃) Lit. (S, 96.5% ee)[α]_(D)=+46 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl_(3,) 6.1:1 mixture ofrotamers) δ 3.35-3.37 (m, 2H), 3.74 (s, 3H), 4.64-4.68(m, 1H), 5.11 (s,2H), 5.41-5.45 (m, 1H), 6.76-6.79(m, 1H), 6.89-6.93 (m, 1H), 7.14-7.16(m, 1H), 7.30-7.39 (m, 5H); ¹H NMR (minor rotamer, partial) δ 3.25-3.33(m, 2H), 3.70 (s, 3H), 4.46-4.56 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ32.48, 52.66, 54.82, 67.17, 125.07, 126.98, 127.19, 128.22, 128.34,128.68, 136.36, 137.23, 155.78, 171.50.

Ethyl (N-Benzyloxycarbonyl) 3-(2-thienyl)alaninate (5e)

¹H NMR (400 MHz, CDCl_(3,) 7.3:1 mixture of rotamers) δ 1.26 (t, J=7.0Hz, 3H), 3.36-3.38 (m, 2H), 4.19 (q, J=7.0 Hz, 2H), 4.61-4.65 (m, 1H),5.12 (s, 2H), 5.40-5.44 (m, 1H), 6.76-6.78 (m, 1H), 6.89-6.92 (m, 1H),7.14-7.16 (m, 1H), 7.31-7.38 (m, 5H); ¹H NMR (minor rotamer, partial) δ3.26-3.32 (m, 2H), 4.48-4.56 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.28,32.53, 54.82, 61.91, 67.16, 125.02, 127.02, 127.14, 128.24, 128.34,128.69, 136.43, 137.32, 155.79, 171.03; IR (CHCl₃) γ 3343, 1732, 1715,1586, 1514, 1457 cm⁻¹; HRMS (DCI) exact mass calcd for (C₁₇H₁₉NO₄S+H⁺)requires m/z 334.1113, found m/z 334.1123.

(N-Benzyloxycarbonyl)-2-aminocaprylic acid (4f)

This product was obtained as a colorless oil in 42% isolated yield and94% ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD column, Hexanes:IPA, 98.4:1.6, 1.0 mL/min, λ 220 nm,t(major, ethyl ester)=18.28 min, t(minor, ethyl ester)=28.54 min] from areaction catalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.56eq. of methanol and was stirred at −60° C. for 37 h when the reactionconversion reached 49%. [α]_(D)=+4.1 (c 0.80, CHCl_(3);) ¹H NMR (400MHz, CDCl₃, 3.4:1 mixture of rotamers) δ 0.87 (t, J=6.7 Hz, 3H),1.14-1.44 (m, 8H), 1.62-1.76 (m, 1H), 1.76-1.96 (m, 1H), 4.35-4.45 (m,1H), 5.06-5.20 (m, 2H), 5.27 (d, J=7.9 Hz, 1H), 7.28-7.42 (m, 5H); ¹HNMR (minor rotamer, partial) δ 4.20-4.30 (m, 1H), 6.20-6.30 (m, 1H); ¹³CNMR (100 MHz, CDCl₃, major rotamer) δ 14.00, 22.49, 25.08, 28.77, 31.50,32.35, 53.73, 67.12, 128.11, 128.23, 128.53, 136.08, 156.02, 177.70; ¹³CNMR (minor rotamer, partial) δ 54.27, 67.54.

Methyl (N-Benzyloxycarbonyl)-2-aminocaprylate (3f)

This product was obtained as a light yellow oil in 49% isolated yieldand 91% ee as determined by chiral HPLC analysis [Daicel chiralpak ODcolumn, Hexanes:IPA, 98.4:1.6, 1.0 mL/min, λ 220 nm, t(minor)=22.56 min,t(major)=32.41 min]. [α]_(D)=−7.9 (c 1.04, CHCl₃); ¹H NMR (400 MHz,CDCl_(3,) 6.1:1 mixture of rotamers) δ 0.87(t, J=6.7 Hz, 3H), 1.18-1.40(m, 8H), 1.56-1.74 (m, 1H), 1.74-1.88 (m, 1H), 3.74 (s, 3H), 4.37 (dd,J=12.9 and 7.9 Hz, 1H), 5.11 (s, 2H), 5.29 (d, J=7.9 Hz, 1H), 7.28-7.42(m, 5H); ¹H NMR (minor rotamer, partial) δ 3.67 (s, 3H), 4.18-4.30 (m,1H), 4.98-5.06 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.97, 24.46, 25.06,28.76, 31.50, 32.63, 52.24, 53.84, 66.92, 128.07, 128.12, 128.48,136.26, 155.83, 173.10.

Ethyl (N-Benzyloxycarbonyl)-2-aminocaprylate (5f)

¹H NMR (400 MHz, CDCl_(3,) 13:1 mixture of rotamers) δ 0.87 (t, J=6.7Hz, 3H), 1.14-1.44 (m, 11H), 1.56-1.72 (m, 1H), 4.19 (q, J=6.7 Hz, 2H),4.35 (dd, J=12.9 and 7.9 Hz, 1H), 5.11 (s, 2H), 5.28 (d, J=7.9 Hz, 1H),7.27-7.42 (m, 5H); ¹H NMR (minor rotamer, partial) δ 4.96-5.06 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ 13.98, 14.14, 22.47, 25.01, 28.79, 31.52,32.69, 53.90, 61.30, 66.89, 128.07, 128.12, 128.49, 136.30, 155.82,172.61; IR (CHCl₃) γ 3346, 2929, 2859, 1732, 1714, 1520, 1455, 1343,1211, 1046 cm⁻; HRMS (DCI) exact mass calcd for (C₁₈H₂₇NO₄+NH₄ ⁺)requires m/z 322.2018, found m/z 322.2016.

(S)-(N-Benzyloxycarbonyl)p-chlorophenylalanine (4g)

This product was obtained as a colorless oil in 44% isolated yield and91% ee (as an ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD+OJ column, Hexanes:IPA, 80:20, 0.6 mL/min, λ 220 nm,t(minor, ethyl ester)=50.43 min, t(major, ethyl ester)=44.19 min] from areaction catalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55eq. of methanol and was stirred at −78° C. for 72 h when the reactionconversion reached 51%. [α]_(D)=+18.1 (c 0.95, EtOH); Lit. (D)[α]_(D)=−17.0 (c 0.35, EtOH); ¹H NMR (400 MHz, CDCl_(3,) 6.5:1 mixtureof rotamers) δ 3.68-3.74 (m, 1H), 3.91-3.97 (m, 1H), 4.52 (s, 2H),4.52-4.57 (m, 1H), 5.08-5.16 (m, 2H), 5.66-5.71 (m, 1H), 7.24-7.39 (m,10H), 10.10 (s, br., 1H); ¹H NMR (minor rotamer, partial) δ 3.81-3.89(m, 1H), 4.38-4.43 (m, 1H), 6.11-6.17 (m, 1H); ¹³C NMR (100 MHz, CDCl₃)δ 54.37, 67.42, 69.67, 73.66, 127.90, 128.14, 128.31, 128.43, 128.68,128.74, 136.26, 137.33, 156.37, 175.43.

(R)-Methyl-(N-Benzyloxycarbonyl)p-chlorophenylalanine (3g)

This product was obtained as a white solid in 49% isolated yield and 89%ee as determined by chiral HPLC analysis [Daicel chiralpak OJ column,Hexanes:IPA, 85:15, 1.0 mL/min, λ 220 nm, t(major)=33.32 min,t(minor)=38.49 min]. [α]_(D)=−9.0 (c 1.45, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 3.68-3.72 (m, 1H), 3.75 (s, 3H), 3.87-3.91(m, 1H), 4.47 (d,J=12.0 Hz, 1H), 4.48-4.52 (m, 1H), 4.54 (d, J=12.0 Hz, 1H), 5.12 (s,2H), 5.63-5.67 (m, 1H), 7.23-7.39 (m, 10H), ¹³C NMR (100 MHz, CDCl₃) δ52.75, 54.60, 67.23, 69.93, 73.47, 127.80, 128.06, 128.28, 128.37,128.63, 128.72, 136.43, 137.63, 156.19, 170.99; IR (CHCl₃) γ 3344, 1732,1715, 1586, 1515, 1454 cm⁻¹; HRMS (DCI) exact mass calcd for(C₁₇H₁₉NO₄S+H⁺) requires m/z 344.1498, found m/z 344.1505.

Ethyl (N-Benzyloxycarbonyl)p-chlorophenylalanine (5g)

¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.0 Hz, 3H), 3.70 (dd, J=9.2 and2.8 Hz, 1H), 3.89 (dd, J=8.8 and 2.8 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H),4.45-4.56 (m, 2H), 4.48-4.52 (m, 1H), 5.12 (s, 2H), 5.64-5.68 (m, 1H),7.23-7.38 (m, 10 H); ¹³C NMR (100 MHz, CDCl₃), δ 14.31, 54.64, 61.84,67.17, 70.02, 73.45, 127.78, 128.02, 128.26, 128.34, 128.60, 128.71,136.48, 137.67, 156.19, 170.46.

(S)-(N-Benzyloxycarbonyl)valine (4h)

This product was obtained as a white solid in 40% isolated yield and 96%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak AS and OJ column, Hexanes:IPA, 90:10, 0.8 mL/min, λ 220 nm,t(major, ethyl ester)=17.26 min, t(minor, ethyl ester)=19.49 min] from areaction catalyzed by DHQD-PHN (20 mol %). This reaction employed 0.8eq. of methanol and was stirred at 0° C. for 22 h when the reactionconversion reached 59%. [α]_(D)=−0.62 (c 1.43, EtOH); (Literature,[α]_(D) ²⁵=+1.5 (c 5.0, EtOH), for S-enantiomer); ¹H NMR (400 MHz,CDCl₃, 4:1 mixture of rotamers) δ 0.93 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.7Hz, 3H), 2.12-2.32 (m, 1H), 4.36 (dd, J=8.5 and 4.3 Hz, 1H), 5.12 (s,2H), 5.29 (br d, J=8.5 Hz, 1H), 7.26-7.42 (m, 5H), 9.20-10.20 (br, 1H);¹H NMR (minor rotamer, partial) δ 4.14-4.24 (m, 1H), 5.15 (s, 2H), 6.18(br d, J=8.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃), δ 17.31, 18.99, 31.00,58.81, 67.20, 128.14, 128.24, 128.54, 136.08, 156.35, 177.05.

Methyl (R)-(N-Benzyloxycarbonyl)valinate (3h)

This product was obtained as a white solid in 58% isolated yield and 67%ee as determined by chiral HPLC analysis [Daicel chiralpak AS and OJcolumn, 9:1, Hexanes:IPA, 0.8 mL/min, λ 220 nm, t(minor)=24.08 min,t(major)=25.92 min]. [α]_(D)=+11.1 (c 1.40, MeOH); (Literature, [α]_(D)²⁰=−18.9 (c 1.0, MeOH), for S-enantiomer); ¹H NMR (400 MHz, CDCl₃, 7:1mixture of rotamers) δ 0.96 (d, J=7.3 Hz, 3H), 2.06-2.20 (m, 1H), 3.73(s, 3H), 4.31 (dd, J=8.5 and 4.9 Hz, 1H), 5.11 (s, 2H), 5.32 (br dd,J=8.5 Hz, 1H), 7.28-7.40 (m, 5H); ¹H NMR (minor rotamer, partial) δ3.68(s, 3H), 4.10-4.20 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 17.48, 18.87,31.23, 52.06, 58.97, 66.97, 128.07, 128.12, 128.47, 136.21, 156.17,172.49.

Ethyl (N-Benzyloxycarbonyl)valinate (5h)

¹H NMR (400 MHz, CDCl₃) δ 0.89 (d, J=7.3 Hz, 3H), 0.97 (d, J=6.7 Hz,3H), 1.28 (t, J=7.3 Hz, 3H), 2.04-2.22 (m, 1H), 4.21 (q, 7.3 Hz, 2H),4.29 (dd, J=8.5 and 4.3 Hz, 1H), 5.11 (s, 3H), 5.31 (br d, J=8.5 Hz,1H), 7.28-7.42 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 14.16, 17.43, 18.88,31.29, 58.95, 61.18, 66.94, 128.08, 128.12, 128.48, 136.26, 156.18,171.97.

(S)-(N-Benzyloxycarbonyl)phenylglycine (4i)

This product was obtained as a white solid in 46% isolated yield and 84%ee (as a methyl ester) as determined by chiral HPLC analysis [Regis(R,R)Whelk-O 1 Reversible Column, Hexanes:IPA, 90:10, 1.0 mL/min, λ 220nm, t(minor, methyl ester)=16.69 min, t(major, methyl ester)=24.76 min]from a reaction catalyzed by (DHQD)₂AQN (10 mol %). This reactionemployed 0.55 eq. of ethanol and was stirred at −78° C. for 16 h whenthe reaction conversion reached 46%. [α]_(D)=+95.6 (c 0.79, 95% EtOH);(Literature, [α]_(D) ²⁵=+116.4 (c 1.0, 95% EtOH), for S-enantiomer); ¹HNMR (400 MHz, CDCl₃) δ 5.06 (s, 2H), 5.18 (d, J=8.5 Hz, 1H), 7.24-7.44(m, 10H), 8.15 (d, J=8.5 Hz, 1H); ¹³C NMR (100 MHz DMSO-d6) δ 58.05,65.60, 127.75, 127.84, 127.93, 128.35, 128.43 (two carbons on thearomatic ring were overlapped), 136.92, 137.10, 155.87, 172.08.

(R)-Ethyl-(N-Benzyloxycarbonyl)pheylglycinate (3i)

This product was obtained as a white solid in 45% isolated yield and 97%ee as determined by chiral HPLC analysis [Regis (R, R) Whelk-O 1Reversible Column, Hexanes:IPA, 90:10, 1.0 mL/min, λ 220 nm,t(major)=14.04 min, t(minor)=22.80 min]. [α]_(D)=−93.1 (c 0.95, CHCl₃);¹H NMR (400 MHz. CDCl_(3,) 5:1 mixture of rotamers) δ 1.20 (t, J=7.3 Hz,3H), 4.04-4.24 (m, 2H), 5.06 (d, J=12.2 Hz, 1H), 5.12 (d, J=12.2 Hz,1H), 5.36 (d, J=7.3 Hz, 1H), 5.87 (d, J=7.3 Hz, 1H), 7.25-7.44 (m, 10H);¹H NMR (minor rotamer, partial) δ 5.18-5.30 (m, 1H), 5.68-5.76 (m, 1H),7.08-7.20 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.96, 57.97, 61.91,67.08, 127.07, 128.15 (br, 2Cs), 128.88, 136.14, 136.77, 155.32, 170.76.

Methyl (N-Benzyloxycarbonyl)pheylglycinate

¹H NMR (400 MHz, CDCl_(3,) 5:1 mixture of rotamers) δ 3.72 (s, 3H), 5.07(d, J=8.2 Hz, 1H), 5.12 (d, J=8.2 Hz, 1H), 5.38 (d, J=7.3 Hz, 1H), 5.85(d, J=7.3 Hz, 1H), 7.25-7.38 (m, 10H); ¹H NMR (minor rotamer, partial) δ3.66 (s, 3H), 5.20-5.28 (m, 1H), 5.64-5.74 (m, 1H), 7.06-7.18 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ 52.79, 57.90, 67.11, 121.12, 128.15, 128.19,128.51, 128.58, 128.95, 136.10, 136.57, 155.31, 171.26.

(S)-(N-Benzyloxycarbonyl)-p-chlorophenylalanine (4j)

This product was obtained as a white solid in 41% isolated yield and 95%ee (as an ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD+Hypersil column, Hexanes:IPA, 96.8:3.2, 1.0 mL/min, λ 220nm, t(minor, methyl ester)=52.49 min, t(major, methyl ester)=61.61 min]from a reaction catalyzed by (DHQD)₂AQN (10 mol %). This reactionemployed 0.55 eq. of ethanol and was stirred at −78° C. for 85 h whenthe reaction was quenched at the conversion of 56%. [α]_(D)=+105 (c1.14, CHCl₃); ¹H NMR (400 MHz, CDCl_(3,) 1.9:1 mixture of rotamers) δ3.71(s, 3H), 5.03 (s, 2H), 5.28-5.33 (m, 1H), 5.97-6.02 (m, 1H),6.79-6.85 (m, 2H), 7.17-7.33 (m, 7H), 8.76 (s, br., 1H); ¹H NMR (minorrotamer, partial) δ 3.75 (s, 3H), 4.93-5.08 (m, 2H), 5.15-5.20 (m, 1H),6.97-7.04 (m, 2H), 7.59-7.64 (m, 1H), ¹C NMR (100 MHz, CDCl₃) δ 55.36,57.38, 67.35, 114.46, 127.74, 128.24, 128.31, 128.37, 128.62, 136.07,155.80, 159.85, 174.73; ¹³C NMR (minor rotamer, partial) δ 57.95, 67.67,114.29, 129.27, 135.07, 156.92, 159.73, 173.92; IR (CHCl₃) γ 3348, 1732,1715, 1611, 1586, 1513, 1455 cm⁻¹; HRMS (DCI) exact mass calcd for(C₁₇H₁₇NO₅+H⁺) requires m/z 316.1185, found m/z 316.1173.

(R)-Methyl-(N-Benzyloxycarbonyl)p-chlorophenylalanine (3j)

This product was obtained as a colorless oil in 55% isolated yield and74% ee as determined by chiral HPLC analysis [Daicel chiralpakOD+Hypersil column, Hexanes:IPA, 96.8:3.2, 1.0 mL/min, λ 220 nm,t(major)=43.45 min, t(minor)=48.95 min]. [α]_(D)=−68 (c 1.61, CHCl₃); ¹HNMR (400 MHz, CDCl_(3,) 7.5:1 mixture of rotamers) δ 1.19 (t, J=7.4 Hz,3H), 3.77 (s, 3H), 4.08-4.23 (m, 2H), 5.06 (d, J=12.4 Hz, 1H), 5.11 (d,J=12.4 Hz, 1H), 5.28-5.31 (m, 1H), 5.87-5.90 (m, 1H), 6.86 (d, J=8.4 Hz,2H), 7.24-7.36 (m, 7H); ¹H NMR (minor rotamer, partial) δ 5.13-5.18 (m,1H), 5.57-5.63 (m, 1H), 7.13-7.19 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ14.11, 55.37, 57.54, 61.92, 67.12, 114.38, 128.28, 128.50, 128.62,128.97, 136.33, 155.49, 159.79, 171.16; IR (CHCl₃) γ 3354, 1732, 1715,1612, 1587, 1514, 1455 cm⁻¹; HRMS (DCI) exact mass calcd for(C₁₉H₂₁NO₅+H⁺) requires m/z 344.1498, found m/z 344.1501.

Ethyl (N-Benzyloxycarbonyl)p-chlorophenylalanine (5j)

¹H NMR (400 MHz, CDCl_(3,) 6.8:1 mixture of rotamers) δ 3.69 (s, 3H),3.76 (s, 3H), 5.04 (d, J=12.2 Hz, 1H), 5.10 (d, J=12.2 Hz, 1H),5.29-5.34 (m, 1H), 5.88-5.91 (m, 1H), 6.86 (d, J=8.4 Hz, 2H), 7.24-7.36(m, 7H); ¹H NMR (minor rotamer, partial) δ 3.60-3.66 (m, 3H), 5.14-5.20(m, 1H), 5.68-5.74 (m, 1H), 7.13-7.19 (m, 1H); ¹³C NMR (100 MHz, CDCl₃)δ 52.84, 55.38, 57.47, 67.16, 114.45, 128.28, 128.55, 128.62, 128.76,136.29, 155.49, 159.87, 171.68; IR (CHCl₃) γ 3357, 1732, 1714, 1613,1586, 1514, 1452 cm⁻¹; HRMS (DCI) exact mass calcd for (C₁₈H₁₉NO₅+H⁺)requires m/z 330.1341, found m/z 330.1331.

(S)-N-(9-Fluorenylmethoxycarbonyl)phenylalanine (4k)

This product was obtained as a white solid in 47% isolated yield and 96%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD column, Hexanes:IPA, 80:20, 1.0 mL/min, λ 254 nm, t(major,ethyl ester)=27.48 min, t(minor, ethyl ester)=17.22 min] from a reactioncatalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55 eq. ofmethanol and was stirred at −78° C. for 46 h when the reactionconversion reached 51%. [α]_(D)=−35.2 (c 1.27, DMF); (Literature,[α]_(D) ²⁰=−37 (c 1.0, DMF), for S-enantiomer); ¹H NMR (400 MHz,acetone-d6, 6:1 mixture of rotamers) δ 3.04 (dd, J=14.0 and 9.5 Hz, 1H),3.25 (dd, J=14.0 and 4.9 Hz, 1H), 4.15-4.24 (m, 1H), 4.24-4.34 (m, 1H),4.49-4.57 (m, 1H), 6.72 (d, J=7.9 Hz, 1H), 7.19-7.26 (m, 1H), 7.26-7.36(m, 5H), 7.36-7.44 (m, 2H), 7.58-7.70 (m, 2H), 7.85 (d, J=7.9 Hz, 2H);¹H NMR (minor rotamer, partial) δ 2.86-2.96 (m, 1H), 3.10-3.18 (m, 1H),4.40-4.49 (m, 1H), 6.08-6.18 (m, 1H); ¹³C NMR (100 MHz, acetone-d6) δ38.13, 47.89, 56.16, 67.11, 120.72, 126.08, 126.14, 127.40, 127.87,128.45, 129.13, 130.14, 138.40, 142.02, 144.94, 156.74, 173.29.

(R)-Methyl-N-(9-Fluorenylmethoxycarbonyl)phenylalaninate (3k)

This product was obtained as a white solid in 50% isolated yield and 92%ee as determined by chiral HPLC analysis [Daicel chiralpak OJ column,Hexanes:IPA, 80:20, 1.0 mL/min, λ 254 nm, t(major)=24.91 min,t(minor)=19.70 min] [α]_(D)=−33.1 (c 1.50, CHCl₃); ¹H NMR (400 MHz,CDCl₃, 6:1 mixture of rotamers) δ 3.08-3.20 (m, 2H), 3.72 (s, 3H),4.12-4.24 (m, 1H), 4.28-4.38 (m, 1H), 4.38-4.54 (m, 1H), 4.67 (dd,J=14.0 and 6.1 Hz, 1H), 5.26 (d, J=8.5 Hz, 1H), 7.04-7.14 (m, 2H),7.20-7.35 (m, 5H), 7.35-7.44 (m, 2H), 7.49-7.60 (m, 2H), 7.76 (d, J=7.3Hz, 2H); ¹H NMR (minor rotamer, partial) δ 2.82-2.90 (m, 2H), 3.66 (s,3H), 4.02-4.08 (m, 1H), 4.88-4.98 (m, 1H), 6.95-7.02 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 38.19, 47.12, 52.34, 54.73, 66.90, 119.96, 125.02,125.08, 127.03, 127.14, 127.69, 128.59, 129.27, 135.66, 141.28, 143.70,155.50, 171.90.

Ethyl N-(9-Fluorenylmethoxycarbonyl)phenylalaninate (5k)

¹H NMR (400 MHz, CDCl₃, 5.6:1 mixture of rotamers) δ 1.25 (t, J=7.3 Hz,3H), 3.05-3.18 (m, 2H), 4.08-4.26 (m, 3H), 4.30-4.40 (m, 1H), 4.40-4.52(m, 1H), 5.28 (d, J=7.9 Hz, 1H), 7.06-7.16 (m, 2H), 7.22-7.37 (m, 5H),7.37-7.46 (m, 2H), 7.50-7.62 (m, 2H), 7.77 (d, J=7.3 Hz, 2H); ¹H NMR(minor rotamer, partial) δ 2.82-2.92 (m, 2H), 4.89-4.99 (m, 1H),6.97-7.04 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 14.09, 38.29, 47.15,54.76, 61.54, 66.90, 119.97, 125.05, 127.04, 127.70, 128.54, 129.37,135.76, 141.29, 143.73, 155.51, 171.46.

(S)-(N-t-Butyloxycarbonyl)phenylalanine (4l)

This product was obtained as a white solid in 41% isolated yield and 98%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak OD and OJ column, Hexanes:IPA, 99:1, 0.8 mL/min, λ 220 nm,t(minor, ethyl ester)=27.73 min, t(major, ethyl ester)=33.26 min] from areaction catalyzed by (DHQD)₂AQN (20 mol %). This reaction employed 1.0eq. of methanol and was stirred at −40° C. for 15 h when the reactionconversion reached 59%. The reaction was quenched with 5% HOAc (2 mL)and the organic layer was washed with 0.2 N HCl (2×1 mL), concentratedunder reduced pressure, dissolved in a mixture of H₂O/THF (v/v: 1/4) andstirred at room temperature overnight. The solvents were removed undervacuum and the residue was dissolved in ether (10 mL) and extracted with1N Na₂CO₃ (3 mL). The organic layer was washed with saturated brine (1mL), dried over anh. Na₂SO₄, filtered and concentrated under vacuum togive methyl ester as a white solid. The basic aq. phase was acidifiedwith 0.5 N HCl till pH<4, then extracted with ethyl acetate (3×4 mL),the combined extract was dried over anh. Na₂SO₄, filtered andconcentrated to give the acid as a white solid. [α]_(D)=−4.2 (c 0.91,AcOH); (Literature, [α]_(D)=−4.0 (c 4.0, AcOH), for S-enantiomer) ¹H NMR(400 MHz, CDCl₃, 2:1 mixture of rotamers) δ 1.42 (s, 9H), 3.00-3.28 (m,2H), 4.54-4.70 (m, 1H), 4.98 (d, J=6.7 Hz, 1H), 7.12-7.40 (m, 5H),7.70-8.70 (br, 1H); ¹H NMR (minor rotamer, partial) δ 1.30 (s, 9H),2.84-3.00 (m, 1H), 4.34-4.50 (m, 1H), 6.30-6.42 (m, 1H); ¹³C NMR (100MHz, CDCl₃, major rotamer) δ 28.26, 37.79, 54.28, 80.29, 127.07, 128.58,129.37, 135.82, 155.37, 176.46; ¹³C NMR (minor rotamer, partial). δ28.03, 39.06, 56.03, 81.52, 136.34, 156.24.

(R)-Methyl-(N-t-Butyloxycarbonyl)phenylalaninate (3l)

This product was obtained as a white solid in 56% isolated yield and 67%ee as determined by chiral HPLC analysis [Daicel chiralpak OD and OJcolumn, Hexanes:IPA, 99:1, 0.8 mL/min, λ 220 nm, t(major)=36.73 min,t(minor)=50.30 min]. [α]_(D)=−27.7 (c 1.11, CHCl₃); ¹H NMR (400 MHz,CDCl_(3,) 5.4:1 mixture of rotamers) δ 1.42 (s, 9H), 3.00-3.18 (m, 2H),3.72 (s, 3H), 4.59 (dd, J=14.0 and 6.1 Hz, 1H), 4.97 (d, J=7.3 Hz, 1H),7.12 (d, J=7.3 Hz, 2H), 7.20-7.36 (m, 3H); ¹H NMR (minor rotamer,partial) δ 2.88-3.00 (m, 2H), 4.36-4.46 (m, 1H), 4.64-4.74 (m, 1H); ¹³CNMR (100 MHz, CDCl₃) δ 28.22, 38.27, 52.10, 54.37, 79.82, 126.94,128.47, 129.22, 135.97, 155.02, 172.29.

Ethyl (N-t-Butyloxycarbonyl)phenylalaninate (5l)

¹H NMR (400 MHz, CDCl_(3,) 5.6:1 mixture of rotamers) δ 1.23 (t, J=6.7Hz, 3H), 1.42 (s, 9H), 3.00-3.16 (m, 2H), 4.16 (q, J=6.7 Hz, 2H), 4.56(dd, J=13.4 and 6.1 Hz, 1H, 4.98 (d, J=7.3 Hz, 1H), 7.14 (d, J=7.3 Hz,2H), 7.20-7.36 (m, 3H); ¹H NMR (minor rotamer, partial) δ 2.88-3.00 (m,2H), 4.30-4.44 (m, 1H), 4.64-4.76 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ14.08, 28.28, 38.39, 54.43, 61.29, 79.80, 126.94, 128.46, 129.34,136.08, 155.07, 171.85.

(S)-(N-Allyloxycarbonyl)phenylalanine (4m)

This product was obtained as a white solid in 45% isolated yield and 91%ee (as a ethyl ester) as determined by chiral HPLC analysis [Daicelchiralpak AS and OD column, Hexanes:IPA, 97:3, 1.0 mL/min, λ 220 nm,t(major, ethyl ester)=39.29 min, t(minor, ethyl ester)=45.34 min] from areaction catalyzed by (DHQD)₂AQN (10 mol %). This reaction employed 0.55eq. of methanol and was stirred at −60° C. for 15 h when the reactionconversion reached 51%. [α]_(D)=+29.5 (c 0.77, CHCl₃); (Literature,[α]_(D)=+35.8 (c 1.0, CHCl₃), for S-enantiomer)¹H NMR (400 MHz, CDCl₃,5:1 mixture of rotamers) δ 3.06-3.28 (m, 2H), 4.48-4.64 (m, 2H),4.64-4.76 (m, 1H), 5.10-5.36 (m, 3H), 5.83-5.96 (m, 1H), 7.18 (d, J=7.3Hz, 2H), 7.22-7.40 (m, 3H), 7.60-7.80 (br, 1H); ¹H NMR (minor rotamer,partial) δ 2.92-3.06 (m, 1H), 4.40-4.48 (m, 1H), 5.74-5.83 (m, 1H); ¹³CNMR (100 MHz, CDCl₃) δ 37.70, 54.48, 66.00, 117.99, 127.26, 128.69,129.30, 132.39, 135.43, 155.74, 176.39; ¹³C NMR (minor rotamer, partial)δ 55.55, 66.40.

(R)-Methyl-(N-Allyloxycarbonyl)phenylalaninate (3m)

This product was obtained as a colorless oil in 44% isolated yield and91% ee as determined by chiral HPLC analysis [Daicel chiralpak ODcolumn, Hexanes:IPA, 98.6:1.4, 1.0 mL/min, λ 220 nm, t(minor)=28.74 min,t(major)=36.38 min]. [α]_(D)=−43.6 (c 0.97, CHCl₃); (Literature,[α]_(D)=+43.3 (c 0.8, CHCl₃), for S-enantiomer) ¹H NMR (400 MHz, CDCl₃)δ 3.00-3.18 (m, 2H), 3.72 (s, 3H), 4.56 (d, J=5.5 Hz, 2H), 4.65 (dd,J=14.0 and 6.1 Hz, 1H), 5.14-5.34 (m, 3H), 5.80-5.96 (m, 1H), 7.12 (d,J=7.3 Hz, 2H), 7.20-7.36 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 38.21,52.26, 54.70, 65.76, 117.75, 127.11, 128.58, 129.21, 132.56, 135.69,155.47, 171.98.

Ethyl (N-Allyloxycarbonyl)phenylalaninate (5m)

¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.0 Hz, 3H), 3.00-3.18 (m, 2H),4.17 (q, J=7.0 Hz, 2H), 4.56 (d, J=5.5 Hz, 2H), 4.63 (dd, J=13.6 and 6.3Hz, 1H), 5.16-5.34 (m, 3H), (d, J=7.8 Hz, 2H), 7.20-7.36 (m, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 14.05, 38.29, 54.73, 61.42, 65.72, 117.73,127.06, 128.52, 129.29, 132.61, 135.77, 155.46, 171.51.

(N-Allyloxycarbonyl)homophenylalanine (4n)

This product was obtained as a colorless oil in 41% isolated yield and96% ee as determined by chiral HPLC analysis [Daicel chiralpak OJcolumn, Hexanes:IPA:TFA, 96:4:0.1, 1.0 mL/min, λ 254 nm, t(minor)=23.55min, t(major)=27.96 min] from a reaction catalyzed by (DHQD)₂AQN (10 mol%). This reaction employed 0.60 eq. of methanol and was stirred at −60°C. for 36 h when the reaction conversion reached 53%. [α]_(D)=+22.7 (c0.67, CHCl₃); ¹H NMR (400 MHz, CDCl₃, 3:1 mixture of rotamers) δ1.96-2.10 (m, 1H), 2.16-2.30 (m, 1H), 2.64-2.80 (m, 2H), 4.38-4.48 (m,1H), 4.59 (d, J=5.5 Hz, 2H), 5.18-5.28 (m, 1H), 5.28-5.40 (m, 2H)5.82-5.98 (m, 1H), 7.12-7.24 (m, 3H), 7.24-7.34 (m, 2H), 7.60-8.60 (br,1H); ¹H NMR (minor rotamer, partial) δ 4.23-4.33 (m, 1H), 6.44-6.54 (m,1H); ¹³C NMR (100 MHz, CDCl₃, major rotamer) δ 31.51, 33.95, 53.44,66.05, 118.03, 126.25, 128.39, 128.52, 132.42, 140.36, 155.95, 176.97;¹³C NMR (minor rotamer, partial) δ 53.64, 66.54; IR (CHCl₃) γ 3319,3027, 2932, 1714, 1698, 1538, 1498, 1455, 1410, 1337 cm⁻¹.

Methyl (N-Allyloxycarbonyl)homophenylalaninate (3n)

This product was obtained as a colorless oil in 54% isolated yield and81% ee as determined by chiral HPLC analysis [J. T. Baker DNBPG(ionic)+Regis (R,R)-Whelk-O1, Hexanes:IPA, 98:2, 0.75 mL/min, λ 220 nm,t(major)=39.80 min, t(minor)=38.21 min]. [α]_(D)=−31.7 (c 0.97, CHCl₃);¹H NMR (400 MHz, CDCl₃, 6.3:1 mixture of rotamers) δ 1.92-2.04 (m, 1H),2.12-2.24 (m, 1H), 2.62-2.74 (m, 2H), 3.72 (s, 3H), 4.36-4.46 (m, 1H),4.59 (d, J=5.5 Hz, 2H), 5.18-5.38 (m, 3H), 5.85-6.00 (m, 1H), 7.15-7.23(m, 3H), 7.25-7.32 (m, 2H); ¹H NMR (minor rotamer, partial) δ 4.24-4.34(m, 1H), 5.10-5.18 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 31.48, 34.21,52.36, 53.53, 65.83, 117.83, 126.18, 128.36, 128.46, 132.57, 140.53,155.72, 172.79; IR (neat) γ 3334, 3028, 2953, 1731, 1715, 1520, 1498,1455, 1335 cm⁻¹.

Ethyl (N-Allyloxycarbonyl)homophenylalaninate (5n)

¹H NMR (400 MHz, CDCl₃, 6.8:1 mixture of rotamers) δ 1.28 (t, J=7.3 Hz,3H), 1.92-2.04 (m, 1H), 2.12-2.24 (m, 1H), 2.60-2.75 (m, 2H), 4.18 (q,J=7.3 Hz, 2H), 4.35-4.45 (m, 1H), 4.59 (d, J=5.5 Hz, 2H), 5.18-5.26 (m,1H), 5.26-5.40 (m, 2H), 5.85-5.98 (m, 1H), 7.13-7.24 (m, 3H), 7.24-7.32(m, 2H); ¹H NMR (minor rotamer, partial) δ 4.23-4.33 (m, 1H), 5.10-5.18(m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.14, 31.47, 34.34, 53.63, 61.47,65.79, 117.79, 126.15, 128.36, 128.46, 132.60, 140.67, 155.72, 172.28;IR (neat) γ 3340, 3025, 2980, 1731, 1715, 1522, 1498, 1455, 1374 cm⁻¹.

INCORPORATION BY REFERENCE

All of the patents and publications cited herein are hereby incorporatedby reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areencompassed by the following claims.

We claim:
 1. A method of performing a kinetic resolution of a racemic mixture or a diastereomeric mixture of a chiral substrate, comprising the steps of: combining a racemic mixture or a diastereomeric mixture of a chiral substrate comprising only a single asymmetric carbon with a nucleophile, in the presence of a chiral non-racemic cinchona-alkaloid-type catalyst, wherein said chiral non-racemic cinchona-alkaloid-type catalyst catalyzes the addition of said nucleophile to said chiral substrate to give a chiral product or unreacted chiral substrate or both enriched in one enantiomer or diastereomer.
 2. The method of claim 1, wherein said kinetic resolution is dynamic.
 3. The method of claim 1, wherein said nucleophile is an alcohol, amine or thiol.
 4. The method of claim 1, wherein said chiral non-racemic cinchona-alkaloid-type catalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.
 5. The method of claim 1, wherein said nucleophile is an alcohol, amine or thiol; and said chiral non-racemic cinchona-alkaloid-type catalyst is quinidine, (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQ)₂PYR, (DHQD)₂PYR, (DHQ)₂AQN, (DHQD)₂AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.
 6. The method of claim 1, wherein the enantiomeric or diastereomeric excess of the product or unreacted substrate is greater than about 50%.
 7. The method of claim 1, wherein the enantiomeric or diastereomeric excess of the product or unreacted substrate is greater than about 70%.
 8. The method of claim 1, wherein the enantiomeric or diastereomeric excess of the product or unreacted substrate is greater than about 90%. 